Quinazoline compound for egfr inhibition

ABSTRACT

Disclosed is a novel quinazoline compound. Specifically, disclosed are a compound represented by the formula (I) and a pharmacologically acceptable salt.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a national stage application of PCT/CN2017/119993,which claims priority to Chinese patent application CN201611259071.9filed on Dec. 30, 2016, the content of which is hereby incorporated intothis application.

TECHNICAL FIELD

The present invention relates to a class of quinazoline compounds asEGFR inhibitors, and their use in the treatment of brain metastatases.In particular, the present invention relates to a compound of formula(I) or (and) a pharmaceutically acceptable salt thereof as an EGFRmutation inhibitor for the treatment of brain metastases.

BACKGROUND ART

Lung cancer is one of the most common malignant tumors in the world, andhas become the leading cause of malignant tumor-related deaths in urbanareas in China. Non-small cell lung cancer (NSCLC) accounts for about80% of all lung cancers, about 75% of patients are at an advanced stageat the time of diagnosis, and the 5-year survival rates are very low.Genetic aberrations in the tyrosine kinase domain of epidermal growthfactor receptor (EGFR) have been identified as one of the key drivers ofNSCLC progression.

EGFR (epidermal growth factor receptor, ErbB-1 or HER1 for short) is amember of the epidermal growth factor receptor (HER) family. The familyincludes HER1 (erbB 1, EGFR), HER2 (erbB2, NEU), HER3 (erbB3) and HER4(erbB4). EGFR is a glycoprotein that is a receptor of epidermal growthfactor (EGF) cell proliferation and signal transduction, belonging to afamily of receptor tyrosine kinases, penetrating cell membranes andlocated on the surfaces of cell membranes. After ligand binding withepidermal growth factor receptor (EGFR), the receptor dimerizationoccurs, which includes the binding of two homomeric receptor molecules(homodimerization), and the binding of different human EGF-relatedreceptor (HER) tyrosine kinase family members (heterodimerization).After EGFR dimerization, the kinase pathway in cells can be activated,including the active sites of Y992, Y1045, Y1068, Y1148, Y1173, etc.This autophosphorylation can lead to downstream phosphorylation,including the MAPK, Akt and JNK pathways, and induce cell proliferation.

EGFR is involved in tumor cell proliferation, angiogenesis, tumorinvasion, metastasis and inhibition of tumor cell apoptosis. Studieshave shown that there is high or abnormal expression of EGFR in manysolid tumors. EGFR overexpression or activation mutation involves in thedevelopment and progress of many human malignant tumors. At present,many small molecule tyrosine kinase inhibitors (TKI) have been developedto target the ATP-binding domain of EGFR. Some of these inhibitors havebeen approved for clinical use. However, EGFR-TKI resistance mayeventually develop after varying periods of treatment, and aboutone-third of patients develop CNS metastasis after acquisition ofEGFR-TKI resistance.

Brain metastasis has become the leading cause of deaths in the course oflung cancer. It has been reported that the incidence of brain metastasisin patients with lung cancer is as high as 30%-50%. After brainmetastasis from lung cancer, it is suggested that the lesion isadvanced, and the average survival time of untreated patients with brainmetastasis is only 1-2 months. The main treatments for brain metastasisfrom lung cancer are surgery, radiation therapy and drug therapy(including targeted drugs and chemotherapy). For patients with brainmetastases, selective use of radiation therapy and surgery are themainstay treatment but offer limited benefits. Surgery is mainly usedfor single tumors or rescue treatment in critical situations. Radiationtherapy and drug therapy are the main methods. Whole-brain radiationtherapy has become a standard treatment for brain metastases, especiallyfor patients with multiple brain metastases and elderly patients in poorgeneral condition. Radiation therapy can help patients to relievesymptoms, with an overall remission rate of 88%. Whole-brain radiationtherapy can effectively improve the neurological symptoms and functionsof patients and quality of life, and the median survival time rangesfrom 3 to 6 months. However, due to the existence of blood-brain barrier(BBB), many drugs can not reach effective therapeutic concentrations, sothese drugs can not meet the market demand.

The blood-brain barrier (BBB) exists at the interface between the brainand the capillaries of brain tissues, which has very complexmulticellular tissues, composed of brain endothelial cells that lineblood vessels and form brain capillary endothelium, and peripheral cellsincluding pericytes, astrocytes and neurons. BBB provides a completelyautonomous environment for cells in CNS, allowing selective access tonutrients and hormones required, while removing waste and reducingexposure to potentially harmful exogenous substances. Most of CNS drugsare small molecules which pass through BBB via passive transcellulardiffusion. In order to achieve efficacy in CNS and the surroundingenvironment, it is necessary to design EGFR inhibitors with thesufficient ability to cross BBB to achieve effective therapeuticconcentrations in the brain.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof,

wherein,

-   R₁ and R₂ are independently selected from H, halogen, OH, CN, NH₂,    respectively, or selected from C₁₋₅ alkyl and C₁₋₅ heteroalkyl, C₁₋₅    alkyl and C₁₋₅ heteroalkyl being optionally substituted with one,    two or three R;-   or, R₁ is connected with R₂ to form a 4-6-membered ring substituted    with two R₅;-   L₁ is selected from a single bond, —(C(R)₂)_(m)—, —O(C(R)₂)_(m)—,    —S(C(R)₂)_(m)—;-   m is independently selected from 0, 1, or 2, respectively;

R₅ is independently selected from H, halo, OH, CN, NH₂, respectively, orindependently selected from C₁₋₅ alkyl, C₁₋₅ heteroalkyl, C₃₋₆cycloalkyl and 3-6-membered heterocycloalkyl, C₁₋₅ alkyl, C₁₋₅heteroalkyl, C₃₋₆ cycloalkyl and 3-6-membered heterocycloalkyl beingoptionally substituted with one, two or three R;

-   R₃ is H, or selected from C₁₋₃ alkyl and C₁₋₃ heteroalkyl, C₁₋₃    alkyl and C₁₋₃ heteroalkyl being optionally substituted with one,    two or three R;-   L₂ is selected from the group consisting of a single bond, —O—,    —NH—;-   L₃ is —C(R)₂—;-   ring A is selected from the group consisting of phenyl,    5-10-membered heteroaryl; R₄ is independently selected from the    group consisting of H, halo, C₁₋₃ alkyl, C₁₋₃ heteroalkyl, C₂₋₃    alkynyl, respectively;-   R is independently selected from H, OH, CN, NH₂, halo, respectively,    or selected from C₁₋₃ alkyl and C₁₋₃ heteroalkyl, C₁₋₃ alkyl and    C₁₋₃ heteroalkyl being optionally substituted with one, two or three    R′;-   the “hetero” of said C₁₋₅ heteroalkyl, said C₁₋₃ heteroalkyl, said    3-6-membered heterocycloalkyl, said 5-9-membered heteroaryl is    selected from the group consisting of —O—, ═O, N, —NH—, —S—, ═S,    —S(═O)—, —S(═O)₂—, —C(═O)O—, —C(═O)NH—, —S(═O)NH—;-   R′ is selected from the group consisting of F, Cl, Br, I, OH, CN,    NH₂;    in any of the above cases, the number of heteroatoms or    heteroatom-containing groups is independently selected from 1, 2 or    3, respectively.

In some aspects of the present invention, the R is selected from thegroup consisting of H, F, Cl, Br, OH, CN, NH₂, CH₃, CH₃CH₂, CH₃O, CF₃,CHF₂, CH₂F.

In some aspects of the present invention, the R₁ and R₂ areindependently selected from H, halogen, OH, CN, NH₂, respectively, orselected from CH₃, CH₃CH₂, CH₃O, CH₃NH, (CH₃)₂N, (CH₃)₂NCH₂ and CH₃OCH₂,CH₃, CH₃CH₂, CH₃O, CH₃NH, (CH₃)₂N, (CH₃)₂NCH₂ and CH₃OCH₂ beingoptionally substituted with one, two or three R.

In some aspects of the present invention, the R₁ and R₂ areindependently selected from the group consisting of H, F, Cl, Br, OH,CN, NH₂, CH₃, CH₃CH₂, CH₃O, CH₃NH, (CH₃)₂N, (CH₃)₂NCH₂, CH₃OCH₂,respectively.

In some aspects of the present invention, the L₁ is selected from asingle bond, —O—, —S—, —C(R)₂—, —(C(R)₂)₂—, —OC(R)₂—, —O(C(R)₂)₂—.

In some aspects of the present invention, the L₁ is selected from asingle bond, —O—, —S—, —CH₂—, —(CH₂)₂—, —CH₂O—, —(CH₂)₂O—.

In some aspects of the present invention, the structural unit

is selected from:

In some aspects of the present invention, the structural unit

is selected from:

In some aspects of the present invention, the structural unit

is selected from:

In some aspects of the present invention, the structural unit

is selected from:

In some aspects of the present invention, the R₅ is independentlyselected from H, F, Cl, Br, OH, CN, NH₂, respectively, or selected fromCH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O, CH₃OCH₂, N(CH₃)₂, NH(CH₃),

CH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O, CH₃OCH₂, N(CH₃)₂, NH(CH₃),

being optionally substituted with one, two or three R.

In some aspects of the present invention, the R₅ is independentlyselected from the group consisting of F, Cl, Br, OH, CN, NH₂, CH₃,CH₃CH₂, CH₂CH₂F, CH₃CH₂CH₂, CH₃O, CH₃OCH₂, N(CH₃)₂,

respectively.

In some aspects of the present invention, the structural unit

is selected from:

In some aspects of the present invention, the R₃ is selected from H,CH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O and CH₃OCH₂, or selected from CH₃, CH₃CH₂,CH₃CH₂CH₂, CH₃O and CH₃OCH₂, CH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O and CH₃OCH₂being optionally substituted with one, two or three R.

In some aspects of the present invention, the R₃ is selected from thegroup consisting of H, CH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O, CHF₂O, CH₃OCH₂.

In some aspects of the present invention, the R₄ is independentlyselected from the group consisting of H, F, Cl, Br, I, CH₃, CH₃O andCH≡C—, respectively.

In some aspects of the present invention, the ring A is selected fromthe group consisting of phenyl, thienyl, pyrrolyl, furyl, pyridyl,indolyl and benzimidazolyl.

In some aspects of the present invention, the

is selected from:

In some aspects of the present invention, the R is selected from thegroup consisting of H, F, Cl, Br, OH, CN, NH₂, CH₃, CH₃CH₂, CH₃O, CF₃,CHF₂, CH₂F, and other variables are as defined above.

In some aspects of the present invention, the R₁ and R₂ areindependently selected from H, halogen, OH, CN, NH₂, respectively, orselected from CH₃, CH₃CH₂, CH₃O, CH₃NH, (CH₃)₂N, (CH₃)₂NCH₂ and CH₃OCH₂,CH₃, CH₃CH₂, CH₃O, CH₃NH, (CH₃)₂N, (CH₃)₂NCH₂ and CH₃OCH₂ beingoptionally substituted with one, two or three R, and other variables areas defined above.

In some aspects of the present invention, the R₁ and R₂ areindependently selected from the group consisting of H, F, Cl, Br, OH,CN, NH₂, CH₃, CH₃CH₂, CH₃O, CH₃NH, (CH₃)₂N, (CH₃)₂NCH₂, CH₃OCH₂,respectively, and other variables are as defined above.

In some aspects of the present invention, the L₁ is selected from asingle bond, —O—, —S—, —C(R)₂—, —(C(R)₂)₂—, —OC(R)₂— and —O(C(R)₂)₂—,and other variables are as defined above.

In some aspects of the present invention, the L₁ is selected from asingle bond, —O—, —S—, —CH₂—, —(CH₂)₂—, —CH₂O— and —(CH₂)₂O—, and othervariables are as defined above.

In some aspects of the present invention, the structural unit

is selected from:

and other variables are as defined above.

In some aspects of the present invention, the structural unit

is selected from:

and other variables are as defined above.

In some aspects of the present invention, the structural unit

is selected from:

and other variables are as defined above.

In some aspects of the present invention, the structural unit

is selected from:

and other variables are as defined above.

In some aspects of the present invention, the R₅ is independentlyselected from H, F, Cl, Br, OH, CN, NH₂, respectively, or selected fromCH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O, CH₃OCH₂, N(CH₃)₂, NH(CH₃),

CH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O, CH₃OCH₂, N(CH₃)₂, NH(CH₃),

being optionally substituted with one, two or three R, and othervariables are as defined above.

In some aspects of the present invention, the R₅ is independentlyselected from the group consisting of F, Cl, Br, OH, CN, NH₂, CH₃,CH₃CH₂, CH₂CH₂F, CH₃CH₂ CH₂, CH₃O, CH₃OCH₂, N(CH₃)₂,

respectively, and other variables are as defined above.

In some aspects of the present invention, the structural unit

is selected from:

and other variables are as defined above.

In some aspects of the present invention, the R₃ is selected from H,CH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O and CH₃OCH₂, or selected from CH₃, CH₃CH₂,CH₃CH₂CH₂, CH₃O and CH₃OCH₂, CH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O and CH₃OCH₂being optionally substituted with one, two or three R, and othervariables are as defined above.

In some aspects of the present invention, the R₃ is selected from thegroup consisting of H, CH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O, CHF₂O, CH₃OCH₂, andother variables are as defined above.

In some aspects of the present invention, the R₄ is independentlyselected from the group consisting of H, F, Cl, Br, I, CH₃, CH₃O andCH≡C—, respectively.

In some aspects of the present invention, the ring A is selected fromthe group consisting of phenyl, thienyl, pyrrolyl, furyl, pyridyl,indolyl and benzimidazolyl, and other variables are as defined above.

In some aspects of the present invention, the

is selected from:

and other variables are as defined above.

In some aspects of the present invention, the compounds are selectedfrom:

wherein, R₁, R₂, R₃, R₄ are as defined above.

In some aspects of the present invention, the compounds are selectedfrom:

wherein, R, R₃, R₄, R₅ are as defined above.

The present invention also provides compounds selected from:

In some aspects of the present invention, the compound is selected from:

The present invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof,

wherein,

R₁ and R₂ are independently selected from t H, halogen, OH, CN, NH₂,respectively, or selected from C₁₋₅ alkyl and C₁₋₅ heteroalkyl, C₁₋₅alkyl and C₁₋₅ heteroalkyl being optionally substituted with one, two orthree R;

-   or, R₁ is connected with R₂ to form a 4-6-membered ring substituted    with two R₅;-   L₁ is selected from a single bond, —(C(R)₂)_(m)—, —O(C(R)₂)_(m)—,    —S(C(R)₂)_(m)—;-   m is independently selected from 0, 1, or 2, respectively;-   R₅ is independently selected from H, halogen, OH, CN, NH₂,    respectively, or independently selected from C₁₋₅ alkyl, C₁₋₅    heteroalkyl, C₃₋₆ cycloalkyl and 3-6-membered heterocycloalkyl, C₁₋₅    alkyl, C₁₋₅ heteroalkyl, C₃₋₆ cycloalkyl and 3-6-membered    heterocycloalkyl being optionally substituted with one, two or three    R; R₃ is H, or selected from C₁₋₃ alkyl and C₁₋₃ heteroalkyl, C₁₋₃    alkyl and C₁₋₃ heteroalkyl being optionally substituted with one,    two or three R;-   L₂ is selected from the group consisting of a single bond, —O—,    —NH—;-   ring A is selected from the group consisting of phenyl,    5-10-membered heteroaryl;-   R₄ is independently selected from the group consisting of H,    halogen, C₁₋₃ alkyl, C₁₋₃ heteroalkyl, C₂₋₃ alkynyl, respectively;

R is independently selected from H, OH, CN, NH₂, halogen, respectively,or selected from C₁₋₃ alkyl and C₁₋₃ heteroalkyl, C₁₋₃ alkyl and C₁₋₃heteroalkyl being optionally substituted with one, two or three R′;

-   the “hetero” of the C₁₋₅ heteroalkyl, C₁₋₃ heteroalkyl, the    3-6-membered heterocycloalkyl, the 5-9-membered heteroaryl group is    selected from the group consisting of —O—, ═O, N, —NH—, —S—, ═S,    —S(═O)—, —S(═O)₂—, —C(═O)O—, —C(═O)NH—, —S(═O)NH—;-   R′ is selected from the group consisting of F, Cl, Br, I, OH, CN,    NH₂;-   in any of the cases, the number of heteroatoms or    heteroatom-containing groups is independently selected from 1, 2 or    3, respectively.

In some aspects of the present invention, the R is selected from thegroup consisting of H, F, Cl, Br, OH, CN, NH₂, CH₃, CH₃CH₂, CH₃O, CF₃,CHF₂, CH₂F.

In some aspects of the present invention, the R₁ and R₂ areindependently selected from H, halogen, OH, CN, NH₂, respectively, orselected from CH₃, CH₃CH₂, CH₃O, CH₃NH, (CH₃)₂N, (CH₃)₂NCH₂ and CH₃OCH₂,CH₃, CH₃CH₂, CH₃O, CH₃NH, (CH₃)₂N, (CH₃)₂NCH₂ and CH₃OCH₂ beingoptionally substituted with one, two or three R.

In some aspects of the present invention, the R₁ and R₂ areindependently selected from the group consisting of H, F, Cl, Br, OH,CN, NH₂, CH₃, CH₃CH₂, CH₃O, CH₃NH, (CH₃)₂N, (CH₃)₂NCH₂, CH₃OCH₂,respectively.

In some aspects of the present invention, the L₁ is selected from asingle bond, —CH₂—, —(CH₂)₂—, —O—, —CH₂O— and —(CH₂)₂O—.

In some aspects of the present invention, the structural unit

is selected from:

In some aspects of the present invention, the structural unit

is selected from:

In some aspects of the present invention, the structural unit

is selected from:

In some aspects of the present invention, the structural unit

is selected from:

In some aspects of the present invention, the R₅ is independentlyselected from H, F, Cl, Br, OH, CN, NH₂, respectively, or selected fromCH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O, CH₃OCH₂, N(CH₃)₂, NH(CH₃),

CH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O, CH₃OCH₂, N(CH₃)₂, NH(CH₃),

being optionally substituted with one, two or three R.

In some aspects of the present invention, the R₅ is independentlyselected from the group consisting of F, Cl, Br, OH, CN, NH₂, CH₃,CH₃CH₂, CH₂CH₂F, CH₃CH₂ CH₂, CH₃O, CH₃OCH₂, N(CH₃)₂,

respectively.

In some aspects of the present invention, the structural unit

is selected from:

In some aspects of the present invention, the R₃ is H, or selected fromCH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O and CH₃OCH₂, CH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃Oand CH₃OCH₂ being optionally substituted with one, two or three R.

In some aspects of the present invention, the R₃ is selected from: H,CH₃, CH₃O.

In some aspects of the present invention, the R₄ is independentlyselected from: H, F, Cl, Br, I, CH₃, CH₃O and CH≡C—, respectively.

In some aspects of the present invention, the ring A is selected from:phenyl, thienyl, pyrrolyl, furyl, pyridyl, indolyl and benzimidazolyl.

In some aspects of the present invention, the structural unit

is selected from:

In some aspects of the present invention, the R is selected from thegroup consisting of H, F, Cl, Br, OH, CN, NH₂, CH₃, CH₃CH₂, CH₃O, CF₃,CHF₂, CH₂F, and other variables are as defined above.

In some aspects of the present invention, the R₁ and R₂ areindependently selected from H, halogen, OH, CN, NH₂, respectively, orselected from CH₃, CH₃CH₂, CH₃O, CH₃NH, (CH₃)₂N, (CH₃)₂NCH₂ and CH₃OCH₂,CH₃, CH₃CH₂, CH₃O, CH₃NH, (CH₃)₂N, (CH₃)₂NCH₂ and CH₃OCH₂ beingoptionally substituted with one, two or three R, and other variables areas defined above.

In some aspects of the present invention, the R₁ and R₂ areindependently selected from the group consisting of H, F, Cl, Br, OH,CN, NH₂, CH₃, CH₃CH₂, CH₃O, CH₃NH, (CH₃)₂N, (CH₃)₂NCH₂, CH₃OCH₂,respectively, and other variables are as defined above.

In some aspects of the present invention, the L₁ is selected from asingle bond, —CH₂—, —(CH₂)₂—, —O—, —CH₂O— and —(CH₂)₂O—, and othervariables are as defined above.

In some aspects of the present invention, the structural unit

is selected from:

and other variables are as defined above.

In some aspects of the present invention, the structural unit

is selected from:

and other variables are as defined above.

In some aspects of the present invention, the structural unit

is selected from:

and other variables are as defined above.

In some aspects of the present invention, the structural unit

is selected from:

and other variables are as defined above.

In some aspects of the present invention, the R₅ is independentlyselected from H, F, Cl, Br, OH, CN, NH₂, respectively, or selected fromCH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O, CH₃OCH₂, N(CH₃)₂, NH(CH₃),

CH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O, CH₃OCH₂, N(CH₃)₂, NH(CH₃),

being optionally substituted with one, two or three R, and othervariables are as defined above.

In some aspects of the present invention, the R₅ is independentlyselected from the group consisting of F, Cl, Br, OH, CN, NH₂, CH₃,CH₃CH₂, CH₂CH₂F, CH₃CH₂ CH₂, CH₃O, CH₃OCH₂, N(CH₃)₂,

respectively, and other variables are as defined above.

In some aspects of the present invention, the structural unit

is selected from:

and other variables are as defined above.

In some aspects of the present invention, the R₃ is H, or selected fromCH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O and CH₃OCH₂, CH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃Oand CH₃OCH₂ being optionally substituted with one, two or three R, andother variables are as defined above.

In some aspects of the present invention, the R₃ is selected from: H,CH₃, CH₃O, and other variables are as defined above.

In some aspects of the present invention, the R₄ is independentlyselected from: H, F, Cl, Br, I, CH₃, CH₃O and CH≡C—, respectively, andother variables are as defined above.

In some aspects of the present invention, the ring A is selected from:phenyl, thienyl, pyrrolyl, furyl, pyridyl, indolyl and benzimidazolyl.

In some aspects of the present invention, the structural unit

is selected from:

and other variables are as defined above.

In some aspects of the present invention, the compound orpharmaceutically acceptable salt thereof is provided, wherein thecompound is selected from:

wherein, R₁, R₂, R₃, R₄ are as defined above.

In some aspects of the present invention, the compound orpharmaceutically acceptable salt thereof is provided, wherein thecompound is selected from:

wherein, R₃, R₄, R₅ are as defined above.

The present invention also has some aspects which are derived fromarbitrary combinations of the variables

The present invention also provides the following compounds, which areselected from:

The present invention also provides a pharmaceutical composition,comprising a therapeutically effective amount of the compound orpharmaceutically acceptable salt thereof or pharmaceutically acceptablecarriers thereof.

The present invention also provides the use of the compound orpharmaceutically acceptable salt thereof or the pharmaceuticalcomposition in preparing drugs for treatment of cancers.

Technical Effects

The present invention relates to a series of novel quinazoline compoundsas EGFR mutation inhibitors, and their use in the treatment of brainmetastatases. The novel quinazoline compounds of the present inventionhave high enzymatic activity and cell line activity against EGFRmutations, as well as good drug-like properties, high permeability andhigh metabolic stability in vitro. Therefore, these compounds mayprovide more effective treatment for EGFR mutant brain metastases.

Definitions and Descriptions

Unless otherwise specified, the following terms and phrases used hereinare intended to have the following meanings. A particular term or phraseshould not be considered uncertain or unclear without a specificdefinition, but should be understood in the ordinary sense. When acommodity name appears in this article, it is intended to refer to thecorresponding commodity or its active ingredients. The term“pharmaceutically acceptable” refers to compounds, materials,compositions and/or formulations that are within a range of reliablemedical judgment and are suitable for contact with the tissues of humanbeings and animals without excessive toxicity, irritation, allergicresponse or other problems or complications, which are compatible withreasonable benefits/risks.

The term “pharmaceutically acceptable salts” refers to the salts of thecompounds of the present invention, which are prepared from thecompounds with specific substituents found by the present invention andrelatively non-toxic acids or bases. When the compounds of the presentinvention contain relatively acidic functional groups, basic additionsalts can be obtained by contacting such compounds in their neutralforms with sufficient bases in pure solutions or appropriate inertsolvents. Pharmaceutically acceptable basic addition salts includesodium salts, potassium salts, calcium salts, ammonium salts, organicammonium salts, magnesium salts or the like. When the compounds of thepresent invention contain relatively basic functional groups, acidaddition salts can be obtained by contacting such compounds in theirneutral forms with sufficient acids in pure solutions or appropriateinert solvents. Examples of pharmaceutically acceptable acid additionsalts include inorganic salts, in which the inorganic acids includehydrochloric acid, hydrobromic acid, nitric acid, carbonic acid,bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogenphosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid,etc., and organic acid salts, in which the organic acids include aceticacid, propanoic acid, isobutyric acid, maleic acid, propanedioic acid,benzoic acid, succinic acid, octanedioic acid, fumaric acid, lacticacid, mandelic acid, phthalic acid, benzenesulfonic acid,p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonicacid, or the like; amino acid (such as arginine, etc.) salts and saltsof organic acid such as glucuronic acid, etc. are also included (seeBerge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science66: 1-19 (1977)). Certain specific compounds of the present inventioncontain basic and acidic functional groups, which can be converted intoany base or acid addition salt.

Preferably, the salts are contacted with bases or acids in aconventional manner, and the parent compounds are separated, therebyregenerating the compounds in their neutral forms. The parent forms ofthe compounds differ from those of various salts in some physicalproperties, e.g. solubilities in polar solvents.

“Pharmaceutically acceptable salts” used herein belong to derivatives ofthe compounds of the present invention, wherein the parent compounds aremodified by forming salts with acids or bases. Examples of thepharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic groups such as amines, alkalimetal salts or organic salts of acidic groups such as carboxylic acidgroups, etc. The pharmaceutically acceptable salts include conventionalnon-toxic salts or quaternary ammonium salts of the parent compounds,such as salts formed from non-toxic inorganic or organic acids.Conventional non-toxic salts include, but are not limited to, saltsderived from inorganic and organic acids. The inorganic or organic acidsare selected from the group consisting of 2-(acetoxy)benzoic acid,2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid,benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citricacid, ethylenediamine tetraacetic acid, ethanedisulfonic acid,ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamicacid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodicacid, hydroxyl, hydroxynaphthalene, isethionic acid, lactic acid,lactose, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid,methanesulfonic acid, nitric acid, oxalic acid, dihydroxynaphthalicacid, pantothenic acid, phenylacetic acid, phosphoric acid,polygalactose aldehyde, propionic acid, salicylic acid, stearic acid,subacetate acid, succinic acid, sulfamic acid, p-aminobenzene sulfonicacid, sulfuric acid, tannin, tartaric acid and p-toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can besynthesized by conventional chemical methods from the parent compoundscontaining acidic or basic functional groups. Generally, the preparationmethod of such salts is: in water, organic solvents, or the mixtures ofboth, the salts are prepared by reacting these compounds in the form offree acids or bases with stoichiometric appropriate bases or acids.Generally, non-aqueous medium, such as ether, ethyl acetate, ethanol,isopropanol or acetonitrile, etc. is preferred.

In addition to salt forms, the present invention also provides compoundsin a prodrug form. The prodrugs of the compounds described herein easilyundergo chemical changes under physiological conditions to be convertedinto the compounds of the present invention. In addition, the prodrugscan be chemically or biochemically converted into the compounds of thepresent invention in vivo environment.

Certain compounds of the present invention can be in non-solvation orsolvation forms, including hydrate forms. Generally speaking, thesolvation forms are equivalent to the non-solvation forms, which are allincluded within the scope of the present invention.

Some compounds of the present invention can contain asymmetric carbonatoms (optical centers) or double bonds. Racemes, diastereoisomers,geometric isomers and single isomers are included within the scope ofthe present invention.

Unless otherwise specified, the absolute configurations of stereocentersare represented by wedged bonds and dashed bonds (

), wave line

represent the wedge bonds or dashed bonds (

or

), and

represent the relative configurations of stereocenters. When thecompounds described herein contain double bonds in olefins or othergeometrically asymmetric centers, unless otherwise specified, theyinclude E and Z geometric isomers. Similarly, all tautomeric forms areincluded within the scope of the present invention.

The compounds of the present invention can exist in specific geometricor stereoisomeric forms. All of such compounds are conceived in thepresent invention, including cis- and trans- isomers, (−)- and (+)-enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers,(L)- isomers, the racemic mixtures thereof, and other mixtures, such asenantiomers or non-enantiomerically enriched mixtures, as falling withinthe scope of the present invention. Additional asymmetric carbon atomsmay be present in a substituent such as an alkyl group. All such isomersand their mixtures are included within the scope of the presentinvention.

Optically active (R)- and (S)- isomers, D and L isomers can be preparedby chiral synthesis or chiral reagents or other conventional techniques.If an enantiomer of a compound of the present invention is to beobtained, it can be prepared by asymmetric synthesis or byderivatization with chiral auxiliaries, in which the resultingnon-enantiomeric mixture is separated and the auxiliary groups are splitto provide the pure enantiomers needed. Alternatively, when themolecules contain basic functional groups (such as amino groups) oracidic functional groups (such as carboxyl groups), the non-enantiomericsalts are formed with appropriate optically active acids or bases, thenthe non-enantiomers are separated by conventional methods known in theart, and the pure enantiomers are recovered. In addition, the separationof the enantiomers and non-enantiomers is usually accomplished bychromatographic methods, which use chiral stationary phases, and areoptionally combined with chemical derivatization (e.g., the formation ofcarbamates from amines).

The compounds of the present invention may contain atomic isotopes innon-natural proportions on one or more atoms constituting the compounds.For example, the compounds can be labeled with radioisotopes, such astritium (³H), iodine-125 (¹²⁵I) or C-14 (¹⁴C). The transformation of allisotope compositions of the compounds of the present invention, whetherradioactive or not, is included within the scope of the presentinvention.

The term “pharmaceutically acceptable carrier” refers to arepresentative carrier for any preparation or carrier medium which candeliver an effective amount of the active substances of the presentinvention, does not interfere with the effectiveness of the biologicalactivity of the active substances and has no toxic side effects on hostsor patients, including water, oil, vegetable and mineral, paste, lotionmatrix, ointment matrix, etc. These matrices include suspensions,tackifiers, penetration enhancers, etc. Their preparations are wellknown to those skilled in the art of cosmetics or topicalpharmaceuticals. For other information about carriers, you can refer toRemington: The Science and Practice of Pharmacy, 21st Ed., Lippincott,Williams & Wilkins (2005), which is incorporated herein by reference.

The term “excipient” usually refers to a carrier, a diluent and/or amedium required for the preparation of an effective pharmaceuticalcomposition.

For pharmaceuticals or pharmacological active agents, the term“effective amount” or “therapeutic effective amount” means a sufficientamount of pharmaceuticals or agents that are non-toxic but can achievethe desired effect. For the oral dosage form in the present invention,the “effective amount” of an active substance in the composition refersto an amount required to achieve the desired effect when combined withanother active substance in the composition. The determination of theeffective amount varies from person to person, depending on age andgeneral condition of a receptor, and also on a specific activesubstance. The appropriate effective amount in a case can be determinedby those skilled in the art according to routine tests.

The term “active ingredient”, “therapeutic agent”, “active substance” or“active agent” refers to a chemical entity that can effectively treattarget disorders, diseases or illnesses.

“Optional” or “optionally” means that the subsequently described eventor circumstance may, but need not, occur, and that the descriptionincludes instances where the event or circumstance occurs and instanceswhere it does not.

The term “substituted” refers to any one or more hydrogen atoms on adesignated atom is replaced with a substituent, which may include heavyhydrogen and variants of hydrogen, as long as the valence state of thespecific atom is normal and the substituted compound is stable. When thesubstituent is a ketone group (i.e., ═O), it means that two hydrogenatoms are substituted. The ketone substitution does not occur on anaromatic group. The term “optionally substituted” means that it may ormay not be substituted, unless otherwise specified, the type and numberof substituents may be arbitrary on the basis of chemical accessibility.

When any variable (e.g., R) occurs more than once in the composition orstructure of a compound, its definition at each occurrence isindependent. Thus, for example, if a group is substituted with 0-2 R,the group can be substituted optionally with at most two R, and R has aseparate option at each occurrence. Furthermore, combinations ofsubstituents and/or their variables are permissible only if suchcombinations result in stable compounds.

When the number of bonding groups is zero, such as —(CRR)₀—, it meansthat the bonding groups are single bonds.

When one of the variables is selected from a single bond, the two groupsattached directly. For example, when L in A-L-Z presents a single bond,it indicates that the structure is actually A-Z.

When a substituent is absent, it means that the substituent does notexist. For example, when X is absent in A-X, it means that the structureis actually A. When a bond to a substituent can cross a bond connectingtwo atoms in a ring, then such substituent may be bonded to any atom onthe ring. When a substituent is listed without indicating the atom viawhich such substituent may be bonded to the compound of general formulaof chemical structure but not specifically mentioned, the substituentsmay be bonded via any atom in such substituent. Combinations ofsubstituents and/or their variables are permissible only if suchcombinations result in stable compounds. For example, a structural unit

may be substituted at any position on a cyclohexyl group orcyclohexadiene.

Unless otherwise specified, the term “hetero” denotes a heteroatom or aheteroatom-containing group (i.e., a group containing heteroatoms),including atoms other than carbon (C) and hydrogen (H), as well asgroups containing these heteroatoms, such as oxygen (O), nitrogen (N),sulfur (S), silicon (Si), germanium (Ge), aluminium (Al), boron (B),—O—, —S—, ═O, ═S, —C(═O)O—, —C(═O)—, —C(═S)—, —S(═O), —S(═O)₂—, andoptionally substituted —C(═O)N(H)—, —N(H)—, —C(═NH)—, —S(═O)₂N(H)— or—S(═O)N(H)—.

Unless otherwise specified, “ring” means substituted or not substitutedcycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl,cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. The so-called ringincludes a single ring, joint ring, spiral ring, parallel ring or bridgering. The number of atoms in a ring is usually defined as the number ofmembers in a ring. For example, a “5, 6, or 7-membered ring” refers tothe arrangement of 5, 6, or 7 atoms in a ring. Unless otherwisespecified, the ring optionally contains 1 to 3 heteroatoms. Therefore, a“5, 6, or 7-membered ring” includes, for example, phenyl, pyridyl andpiperidinyl; on the other hand, the term “5, 6, or 7-memberedheterocycloalkyl ring” includes pyridyl and piperidinyl, but excludesphenyl. The term “ring” also includes a ring system containing at leastone ring, each of which independently coincides with the abovedefinition.

Unless otherwise specified, the term “heterocycle” or “heterocyclicgroup” refers to a stable mono-, bi-, or tri-cyclic ring, containing aheteroatom or heteroatom-containing groups, which may be saturated,partially unsaturated or unsaturated (aromatic), containing carbon atomsand 1, 2, 3 or 4 heteroatoms independently selected from N, O and S,wherein any of the heterocycles may be fused to a benzene ring to form abicyclic ring. The nitrogen and sulfur heteroatoms may be optionallyoxidized (i.e., NO and S(O)p, p is 1 or 2). The nitrogen atom may besubstituted or unsubstituted (i.e., N or NR, where R is H or othersubstituents as already defined herein). The heterocyclic ring may beattached to its pendant group at any heteroatom or carbon atom whichresults in forming a stable structure. If the formed compound is stable,the heterocycle described herein may be substituted on a carbon ornitrogen atom. A nitrogen atom in heterocycle are optionallyquaternized. It is a preferred plan that when the total number of S andO atoms in the heterocycle exceeds 1, these heteroatoms are not adjacentto each other. It is another preferred plan that the total number of Sand O atoms in heterocycle is not more than 1. As used herein, the term“aromatic heterocyclic group” or “heteroaryl” refers to a stable 5-, 6-or 7-membered monocyclic or bicyclic or 7-, 8-, 9- or 10-memberedbicyclic aromatic heterocylic group, which contain carbon atoms and 1,2, 3 or 4 heteroatoms independently selected from N, O and S. Thenitrogen atom may be substituted or unsubstituted (i.e., N or NR, whereR is H or other substituents as already defined herein). The nitrogenand sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)p, pis 1 or 2). It is noteworthy that the total number of S and O atoms inthe aromatic heterocycle is not more than 1. A bridge ring is alsoincluded in the definition of the heterocycle. Abridge ring is formedwhen one or more atoms (i.e., C, O, N or S) attach two non-adjacentcarbon or nitrogen atoms. A preferred bridging ring includes, but is notlimited to, one carbon atom, two carbon atoms, one nitrogen atom, twonitrogen atoms and a carbon-nitrogen group. It is noted that a bridgealways converts a monocyclic ring into a tricyclic ring. In a bridgering, substituents on the ring may also be present on the bridge.

Examples of heterocyclic compounds include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzomercaptofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl,benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl,benzoimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromone, cinnoline decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furastanyl,imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indole alkenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isoindolyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, hydroxyindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, benzoxanthinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, isothiazolylthiophenyl,thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl. Fused rings and spiro compounds are also included.

Unless otherwise specified, the term “hydrocarbyl” or its subordinateconcept (e.g., alkyl, alkenyl, alkynyl, aryl, etc.) by itself or ahydrocarbyl group as part of another substituent, representing astraight, branched or cyclic hydrocarbon group, or their combinations,may be fully saturated (e.g., alkyl), monounsaturated or polyunsaturated(e.g., alkenyl, alkynyl, aryl), may be mono-substituted ormulti-substituted, may be monovalent (e.g., methyl), divalent (e.g.,methylene) or polyvalent (e.g., methine), and may include a divalent orpolyvalent group, with a specified number of carbon atoms (e.g., C₁-C₁₂for 1 to 12 carbons, C₁₋₁₂ selected from C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈,C₉, C₁₀, C₁₁ and C₁₂; C₃₋₁₂ were selected from C₃, C₄, C₅, C₆, C₇, C₈,C₉, C₁₀, C₁₁ and C₁₂.) “Hydrocarbyl” includes but is not limited toaliphatic and aromatic hydrocarbon, wherein the aliphatic hydrocarbylgroup includes a chain and a ring, specifically including but notlimited to alkyl, alkene and alkynyl, and the aromatic hydrocarbyl groupincludes but are not limited to a 6-12-membered aromatic hydrocarbylgroup, such as benzene, naphthalene, etc. In some embodiments, the term“hydrocarbyl” denotes a straight or branched group or theircombinations, which may be fully saturated, monounsaturated orpolyunsaturated, and may include a divalent or polyvalent group.Examples of saturated hydrocarbyl groups include, but are not limitedto, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl,sec-butyl, isobutyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, and homologues or isomers of n-pentyl, n-hexyl, n-heptyl,n-octyl, etc. Unsaturated hydrocarbyl groups contain one or more doubleor triple bonds. Examples include but are not limited to vinyl,2-propylene, butenyl, crotonyl, 2-isoprenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-and 3-propynyl,3-butynyl, and more advanced homologues and isomers.

Unless otherwise specified, the term “heterohydrocarbyl ” or itssubordinate concept (e.g., heteroalkyl, heteroalkenyl, heteroalkynyl,heteroaryl, etc.), by itself or in combination with other terms, means astable straight, branched or cyclic hydrocarbon radical or combinationsthereof, consisting of the stated number of carbon atoms and at leastone heteroatom. In some embodiments, the term “heteroalkyl”, by itselfor in combination with other terms, represents a stable straight,branched hydrocarbyl group or their compositions, consisting of acertain number of carbon atoms and at least one heteroatom. In a typicalembodiment, a heteroatom is selected from B, O, N and S, where thenitrogen and sulfur atoms are optionally oxidized and the nitrogenheteroatom is optionally quaternized. A heteroatom orheteroatom-containing group may occupy any internal position of aheterohydrocarbyl group, including the position where the hydrocarbylgroup is attached to the remainder of the molecule, but the terms“alkoxy”, “alkylamino” and “alkylthio” (or thioalkyl) are conventionallyexpressed, referring to being attached to the remainder of those alkylgroups of a molecule via an oxygen atom, an amino atom or a sulfur atom,respectively. Examples include but are not limited to —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —CH₂—CH═N—OCH₃ and —CH═N(CH₃)—CH₃. Atmost two heteroatoms may be adjacent to one another, for example—CH₂—NH—OCH₃.

Unless otherwise specified, the term “cyclohydrocarbyl”,“heterocyclohydrocarbyl” or its subordinate concept (e.g., aryl,heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, etc.), by itselfor in combination with other terms, represents cyclic “hydrocarbyl” and“heterohydrocarbyl”, respectively. Additionally, for heterohydrocarbylor heterocyclohydrocarbyl (such as heteroalkyl and heterocycloalkyl), aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Examples of cycloalkyl include, butare not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl,3-cyclohexenyl, cycloheptyl, etc. Non-limiting examples ofheterocycloalkyl moieties include 1-(1,2,5,6-tetrahydropyridyl),1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl,3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-indol-3-yl,tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl and2-piperazinyl.

Unless otherwise specified, the term “alkyl” is used to denote astraight or branched saturated hydrocarbon chain, which can bemono-substituted (e.g. —CH₂F) or poly-substituted (e.g. —CF₃), and canbe monovalent (e.g. methyl), divalent (e.g. methylene) or polyvalent(e.g. methine). Examples of alkyl include methyl (Me), ethyl (Et),propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl,s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), etc.

Unless otherwise specified, “alkenyl” refers to an alkyl groupcontaining one or more carbon-carbon double bonds at any point in thechain, which can be mono-substituted or poly-substituted, and can bemonovalent, divalent or polyvalent. Examples of alkenyl groups includevinyl, propylene, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl,hexadienyl, etc.

Unless otherwise specified, “alkynyl” refers to an alkyl groupcontaining one or more carbon-carbon triple bonds at any point in thechain, which can be mono-substituted or poly-substituted, and can bemonovalent, divalent or polyvalent. Examples of alkynyl groups includeacetylene, propynyl, butynyl, pentynyl, etc.

Unless otherwise specified, “cycloalkyl” includes any stable cyclic orpolycyclic hydrocarbon groups, and any carbon atom is saturated, whichcan be mono-substituted or poly-substituted, and can be monovalent,divalent or polyvalent. Examples of these cycloalkyl groups include, butare not limited to, cyclopropyl, norbornyl, bicyclo[2.2.2]octane,bicyclo[4.4.0]decane, etc.

Unless otherwise specified, “cycloalkenyl” includes any stable cyclic orpolycyclic hydrocarbon group containing one or more unsaturatedcarbon-carbon double bonds at any point in the ring, which can bemono-substituted or poly-substituted, and can be monovalent, divalent orpolyvalent. Examples of these cycloaklenyl groups include, but are notlimited to, cyclopentenyl, cyclohexenyl, etc.

Unless otherwise specified, “cycloalkynyl” includes any stable cyclic orpolycyclic hydrocarbon group containing one or more carbon-carbon triplebonds at any point in the ring, which can be mono-substituted orpoly-substituted, and can be monovalent, divalent or polyvalent.

Unless otherwise specified, the term “halo” or “halogen”, by itself oras part of another substituent, represents a fluorine, chlorine, bromineor iodine atom. Additionally, the term “haloalkyl” is intended toinclude monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is intended to include, but not limited to,trifluoromethyl, 2,2-trifluoroethyl, 4-chlorobutyl and 3-bromopropyl,etc. Unless otherwise specified, examples of haloalkyl include, but arenot limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, andpentachloroethyl.

“Alkoxy” represents the-mentioned alkyl group with the specified numberof carbon atoms attached via an oxygen bridge. Unless otherwisespecified, C₁₋₆ alkoxy groups include C₁, C₂, C₃, C₄, C₅ and C₆ alkoxygroups. Examples of the alkoxy groups include, but are not limited to,methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy,tert-butoxy, n-pentyloxy and S-pentyloxy.

Unless otherwise specified, the term “aryl” means a polyunsaturatedaromatic hydrocarbon substitute, which can be mono-substituted orpoly-substituted, can be monovalent, divalent or polyvalent, and can bea single ring or multiple rings (e.g., one to three rings; at least oneof them is aromatic), which are fused together or linked covalently. Theterm “heteroaryl” refers to an aryl group (or a ring) containing fromone to four heteroatoms. In an exemplary embodiment, the heteroatom isselected from B, N, O and S, where the nitrogen and sulfur atoms areoptionally oxidized and the nitrogen atoms are optionally quaternized.The heteroaryl groups can be attached to the remainder of the moleculevia heteroatoms. Non-limiting examples of aryl or heteroaryl groupsinclude phenyl, naphthyl, biphenyl, pyrrolyl, imidazolyl, pyrazinyl,oxazolyl, phenyl-oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl,pyridyl, pyrimidyl, benzothiazolyl, benzimidazolyl, indolyl,isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl,pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl,purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl groups.Substituents for any of the aryl and heteroaryl ring systems areselected from the group of acceptable substituents described below.

Unless otherwise specified, an aryl group in combination with otherterms (e.g., aryloxy, arylsulfur, arylalkyl) includes an aryl andheteroaryl ring as defined above. Therefore, the term “arylalkyl” isintended to include those groups (e.g., benzyl, phenylethyl,pyridylmethyl, etc.) where aryl groups are attached to alkyl groups, andinclude those alkyl groups where carbon atoms (e.g., methylene) havebeen substituted with oxygen atoms, such as phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthoxy)propyl, etc.

The term “leaving group” refers to a functional group or atom that canbe replaced by another functional group or atom via a substitutionreaction (e.g., nucleophilic substitution reaction). For example, therepresentative leaving group includes trifluoromethanesulfonate;chlorine, bromine, iodine; a sulfonate group, such as methyl sulfonate,toluene sulfonate, p-bromobenzene sulfonate, p-toluene sulfonate, etc.;an acyloxy group, such as acetoxyl, trifluoroacetoxyl, etc.

The term “protecting group” includes but is not limited to “aminoprotecting group”, “hydroxyl protecting group” or “thiol protectinggroup”. The term “amino protecting group” refers to a protecting groupsuitable for preventing side reactions on the nitrogen site of aminogroup. Representative amino protection groups include, but are notlimited to, formyl groups; acyl groups, such as alkyl acyl groups (e.g.,acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl groups, suchas tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such asbenzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc);arylmethyl groups, such as benzyl (Bn), triphenylmethyl (Tr), 1,1-bis(4′-methoxyphenyl)methyl; methylsilyl, such as trimethylsilyl (TMS) andtert-butyldimethylsilyl (TBS), etc. The term “hydroxyl protecting group”refers to a protecting group suitable for preventing side reactions on ahydroxyl group. Representative hydroxyl protecting groups include, butare not limited to, alkyl groups such as methyl, ethyl and tert-butylgroups; acyl groups such as alkyl acyl groups (e.g., acetyl groups);arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB),9-fluorenylmethyl (Fm) and diphenylmethyl (DPM); methylsilyl, such astrimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc.

The compounds of the present invention can be prepared by a variety ofsynthesis methods known to those skilled in the art, including thespecific embodiments listed below, the embodiments formed by theircombination with other chemical synthesis methods and the equivalent oralternative methods known to those skilled in the art. The preferredembodiments include but are not limited to the embodiments of thepresent invention.

The solvent used in the present invention is commercially available. Thefollowing abbreviations are used in the present invention: aq stands forwater; HATU stands forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; EDC stands forN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; m-CPBAstands for m-chloroperoxybenzoic acid; eq stands for equivalent orequal; CDI stands for carbonyl diimidazole; DCM stands fordichloromethane; PE stands for petroleum ether; DIAD stands fordiisopropyl azodicarboxylate; DMF stands for N, N-dimethylformamide;DMSO stands for dimethylsulfoxide; EtOAc stands for ethyl acetate; EtOHstands for ethanol; MeOH stands for methanol; CBz stands forbenzyloxycarbonyl, an amine protecting group; BOC stands fortert-butylcarbonyl, an amine protecting group; HOAc stands for aceticacid; NaCNBH₃ stands for sodium cyanoborohydride; r.t. stands for roomtemperature; O/N stands for overnight; THF stands for tetrahydrofuran;Boc₂O stands for di-tert-butyl dicarbonate; TFA stands fortrifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl₂stands for thionyl chloride; CS₂ stands for carbon disulfide; TsOHstands for p-toluenesulfonic acid; NFSI stands forN-fluoro-N-(phenylsulfonyl) benzenesulfonamide; NCS stands for1-chloropyrrolidine-2,5-dione; n-Bu₄NF stands for tetrabutylammoniumfluoride; iPrOH stands for 2-propanol; mp stands for melting point; LDAstands for lithium diisopropylamine.

Compounds are named manually or with ChemDraw® software, andcommercially available compounds are named as in suppliers' catalogues.

Shimadzu LC₂₀AB system with Shimadzu SIL-20A Autosampler and JapaneseShimadzu DAD: SPD-M20A detector was used for high performance liquidchromatography analysis, and Xtimate C₁₈ (3 □m packing material, 2.1×300mm) column was used. A method of 0-60A B_6 minutes: using lineargradient, the elution started with 100% A (A was a 0.0675% T formateaqueous solution) and ended with 60% B (B was 0.0625% T formate MeCNsolution); the whole process was 4.2 minutes, followed by elution with60% B for 1 minute; the column was rebalanced for 0.8 minutes to 100:0,and the total running time was 6 minutes. A method of 10-80A B_6minutes: using linear gradient, the elution started with 90% A (A was0.0675% T formate aqueous solution) and ended with 80% B (B was 0.0625%T formate acetonitrile solution); the whole process was 4.2 minutes,followed by 80% B elution for 1 minute; the column was rebalanced for0.8 minutes to 90:10, and the total running time was 6 minutes. Thecolumn temperature was 50° C. and the flow rate was 0.8 ml/min. Thediode array detectors scanned the wavelength range from 200 to 400 nm.

Thin layer chromatography (TLC) was performed on Sanpont silica gelGF254. Usually ultraviolet light was used to observe spots, and in somecase, other methods were also adopted to observe the spots, by whichiodine (adding about 1 g of iodine into 10 g of silica gel and mixingcompletely), vanillin (dissolving about 1 g of vanillin in 100 ml of 10%H₂SO₄), ninhydrin (purchased from Aldrich) or a special chromogenicreagent (prepared by completely mixing (NH₄)₆Mo₇O₂₄.4H₂O, 5 g(NH₄)₂Ce(IV)(NO₃)₆, 450 ml of H₂O and 50 ml of concentrated H₂SO₄) wasused to develop the thin layer plate and observe the compounds. By themethod similar to that disclosed in Still, W. C., Kahn, M., and Mitra,M. Journal of Organic Chemistry, 1978, 43, 2923-2925, the rapid columnchromatography on Silicycle 40-63 μm (230-400 mesh) silica gel wasperformed. Common solvents used in the rapid column chromatography orTLC were the mixtures of dichloromethane/methanol, ethylacetate/methanol and hexane/ethyl acetate.

On the Gilson-281 Prep LC 322 system, a Gilson UV/VIS-156 detector wasused for chromatographic analysis. The chromatography columns used wereAgella Venusil ASB Prep C18, 5 □m, 150×21.2 mm; Phenomenex GeminiC_(18, 5) □m, 150×30 mm; Bon Symmetrix C_(18, 5) □m, 150×30 mm; orPhenomenex C_(18, 4) □m, 150×30 mm. At a flow rate of about 25 ml/min,the compounds were eluted with low gradient acetonitrile/water, whichcontained 0.05% HCl, 0.25% HCOOH or 0.5% NH₃.H₂O in the water. The totalrunning time was 8-15 minutes.

EXAMPLES

To illustrate the present invention in more detail, the followingexamples are given, but the scope of the present invention is notlimited thereto.

Process A

Example 1 Compound 1A

2-Amino-4-methoxybenzoic acid (5.00 g, 29.91 mmol) was dissolved inacetic acid (10 mL) and acetonitrile (100 mL), slowly added dropwisewith liquid bromine (4.78 g, 29.91 mmol) at 0° C. and under nitrogenprotection, and stirred at 20° C. for 1 hour. TLC showed that thereaction was complete. After the reaction solution was concentrated,water (100 ml) and petroleum ether (100 ml) were successively used formaking a slurry, which was vacuum dried to obtain compound 1A. ¹H NMR(400 MHz, DMSO-d₆) δ=7.76 (s, 1H), 6.41 (s, 1H), 3.79 (s, 3H).

Compound 1B

Compound 1A (5.9 g, 18.94 mmol) and formamidine acetate (3.55 g, 34.10mmol) were dissolved in ethylene glycol monomethyl ether (10 mL), andthe reaction mixture was stirred under nitrogen protection at 120° C.for 3 hours. TLC showed that the reaction was complete. The reactionsolution was cooled down to room temperature, the solids wereprecipitated and filtered, and the filter cake was washed with EA (10mL×2), PE (20 mL×3) and water (50 mL×2), respectively. Compound 1B wasobtained after drying. LCMS (ESI) (5-95AB): m/z: 254.9 [M+1].

Compound 1C

Compound 1B (500 mg, 1.83 mmol) was dissolved in thionyl chloride (6mL), added with DMF (1.34 g, 18.27 mmol, 1.41 mL), stirred undernitrogen protection at 90° C. for 12 hours. The target compound wasdetected by LCMS and TLC showed that the reaction was complete. Thereaction solution was concentrated, then separated and purified bycolumn chromatography (silica gel, EA: PE=0:1, 1:3), to give compound1C. LCMS (ESI) (5-95AB): m/z: 273.0 [M+1].

Compound 1D

Compound 1C (2.47 g, 9.03 mmol) and 3-chloro-2-fluoroaniline (1.31 g,9.03 mmol) were dissolved in isopropanol (30 mL), and the reactionmixture was stirred under nitrogen protection at 60° C. for 2 hours. Thetarget compound was detected by liquid chromatography mass spectrometryand TLC showed that the reaction was complete. The reaction liquid wascooled down to room temperature, added with petroleum ether (40 mL)stirred for half an hour filtered to obtain a solid was and washed withpetroleum ether (30 mL). The solid was slowly added to a sodiumbicarbonate solution (40 mL) and stirred for half an hour, filtered toobtain a solid, which was then washed with water (20 mL) and petroleumether (30 mL), and dried under vaccum to give the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ=8.78 (s, 1H), 8.43 (s, 1H), 7.46 (td, J=7.4, 19.7Hz, 2H), 7.29-7.22 (m, 2H), 4.01 (s, 3H). LCMS (ESI) (5-95AB): m/z:382.1 [M+1].

Compound 1E

4-Cyanopiperidine-1-formic acid tert-butyl ester (3.00 g, 14.27 mmol)was dissolved in tetrahydrofuran (30.00 mL), slowly added dropwise withlithium hexamethyldisilazide (1M, 28.54 mL) at −78° C. and undernitrogen protection, stirred for 1 hour, slowly added dropwise withethyl chloroformate (3.10 g, 28.54 mmol), and then stirred undernitrogen protection at −78° C. for 1 hour. TLC showed that the reactionwas complete. The reaction solution was quenched with a saturatedsolution of sodium bicarbonate (15 mL), and extracted with ethyl acetate(20 mL×2), and the combined organic phases were washed with a saturatedsolution of ammonium chloride (50 mL), dried over anhydrous sodiumsulfate (10 g), filtered and concentrated to give 1E. ¹H NMR (400 MHz,DMSO-d₆) δ=4.23 (q, J=7.1 Hz, 2H), 4.00-3.92 (m, 2H), 2.95 (br, 2H),2.07 (br d, J=13.3 Hz, 2H), 1.89-1.76 (m, 2H), 1.40 (s, 9H), 1.24 (t,J=7.1 Hz, 3H).

Compound 1F

Compound 1E (2.30 g, 8.15 mmol) was dissolved in methanol (15.00 mL),added with sodium borohydride (369.82 mg, 9.78 mmol) at 0° C., andstirred under nitrogen protection at 0-20° C. for 1 hour. TLC showedthat the reaction was complete. After the reaction mixture wasconcentrated, the reaction solution was quenched with a saturatedsolution of sodium bicarbonate (20 mL), and extracted with ethyl acetate(20 mL×2); the combined organic phases were concentrated, separated andpurified by column chromatography (petroleum ether:ethyl acetate=50:1 to5:1) to give 1F. 1H NMR (400 MHz, deuterated chloroform) δ=4.28-4.06 (m,2H), 3.67 (s, 2H), 3.04 (br t, J=12.0 Hz, 2H), 1.96 (br dd, J=1.9, 13.4Hz, 2H), 1.51-1.43 (m, 11H).

Compound 1G

Compound 1F (500.00 mg, 2.08 mmol) was dissolved in methanol (20 mL).Raney nickel (0.2 g) was added into the reaction solution under nitrogenprotection, and the gas in the reaction system was displaced withhydrogen gas three times. The reaction mixture was stirred underhydrogen atmosphere (50 psi) at 30° C. for 2 hours. TLC showed that thereaction was complete. The reaction solution was filtered, concentratedand dried on a rotary evaporator to give 1G. 1HNMR (400 MHz, deuteratedchloroform) δ=3.71 (s, 2H), 3.57 (br d, J=13.3 Hz, 2H), 3.23 (ddd,J=3.5, 9.7, 13.5 Hz, 2H), 2.84 (s, 2H), 1.59-1.51 (m, 2H), 1.46 (s,11H), 1.33 (d, J=4.2, 9.5, 13.6 Hz, 3H).

Compound 1H

Compounds 1G (1.05 g, 4.30 mmol) and triethylamine (1.09 g, 10.74 mmol)were dissolved in dichloromethane (20 mL), with carbon dioxide gaspurged into the reaction solution at −40° C. for 15 minutes, then slowlyadded dropwise with AcCl (212.64 mg, 4.30 mmol) at −40° C. and stirredfor 15 minutes. Finally, the reaction solution was stirred at 20° C. for39.5 hours. TLC showed that the reaction was partly complete. Thereaction solution was concentrated, separated and purified by columnchromatography (dichloromethane:methanol=100:1 to 20:1) to give 1H. ¹HNMR (400 MHz, deuterated chloroform) δ=5.99 (br. s., 1H), 4.07 (s, 2H),3.54-3.48 (m, 2H), 3.39-3.32 (m, 2H), 3.20 (s, 2H), 1.56 (t, J=5.8 Hz,4H), 1.47 (s, 9H).

Compound 1I

Compound 1D (100.0 mg, 261.36 mmol) and Compound 1H (77.72 mg, 287.50mmol) were dissolved in 1,4-dioxane (2 mL), then added with cesiumcarbonate (170.31 mg, 522.73 mmol), cuprous iodide (29.87 mg, 156.82mmol) and N, N′-dimethyl-1,2-ethylenediamine respectively, and stirredunder nitrogen protection at 120° C. for 24 hours. The target compoundwas detected by liquid chromatography mass spectrometry and TLC showedthat the raw materials were not completely consumed. The reactionmixture was filtered with dichloromethane:methanol=10:1 (22 mL), thenconcentrated, separated and purified by TLC(dichloromethane:methanol=20:1) to give 1I. LCMS (ESI) (5-95AB): m/z:572.2 [M+1].

Compound 1J

Compound 11(96.00 mg, 131.91 mmol) was dissolved in dichloromethane (4mL), then added with trifluoroacetic acid (1.2 g, 10.55 mmol) andstirred under nitrogen protection at 20° C. for 1 hour. The targetcompound was detected by liquid chromatography mass spectrometry. Thereaction solution was concentrated under vacuum to give Compound 1J,which would be used directly for the next step. ¹H NMR (400 MHz,METHANOL-d4) δ=8.83 (s, 1H), 8.67 (s, 1H), 7.65-7.51 (m, 3H), 7.35 (brt, J=8.1 Hz, 1H), 4.46 (brs, 2H), 4.23 (s, 4H), 4.17 (s, 3H), 3.76 (brd, J=5.3 Hz, 2H), 2.05 (br d, J=13.2 Hz, 2H), 1.87 (br t, J=5.8 Hz, 7H).LCMS (ESI) (5-95AB): m/z: 472.1 [M+1].

Compound 1

Compound 1J (77.29 mg, 131.91 mmol, trifluoroacetate) was dissolved inmethanol (2.00 mL), added with sodium carbonate (13.98 mg, 131.91 mmol),stirred at 40° C. for 0.5 hours, then added with polyformaldehyde (47.53mg, 527.64 mmol) stirred at 40° C. for 0.5 hours, the added with NaBH₃CN(33.16 mg, 527.64 mmol) and stirred at 40° C. for 1 hour. The targetcompound was detected by liquid chromatography mass spectrometry. Thereaction mixture was filtered by DCM:MeOH=10:1 (22 mL), concentrated,separated and purified by high performance liquid chromatography, togive compound 1 finally. The purity was verified by high performanceliquid chromatography and liquid chromatography mass spectrometrysimultaneously. ¹H NMR (400 MHz, METHANOL-d4) δ=8.46 (s, 1H), 8.32 (s,1H), 7.58 (br t, J=7.0 Hz, 1H), 7.41 (t, J=6.7 Hz, 1H), 7.33 (s, 1H),7.24 (t, J=8.0 Hz, 1H), 4.37 (br d, J=12.7 Hz, 2H), 4.04 (s, 3H), 3.66(br d, J=15.8 Hz, 2H), 3.28-3.19 (m, 2H), 3.11 (br s, 2H), 2.78 (s, 3H),1.94 (br d, J=6.0 Hz, 4H). LCMS (ESI) (5-95AB): m/z: 485.9 [M+1].

Example 2 Compound 2A

Lithium hexamethyldisilazide (1M, 60.23 mL) was added to tetrahydrofuran(60 mL) under nitrogen protection at −78° C., slowly added dropwise withethyl acetate (5.84 g, 66.25 mL) under stirring, then added with4-oxoperidine-1-formic acid tert-butyl ester (10.00 g, 50.19 mmol)dissolved in tetrahydrofuran (40 mL), and stirred at −78-0° C. for 10hours. TLC showed that the reaction was mostly complete. The reactionsolution was concentrated to about 60 mL, added with a saturatedsolution of ammonium chloride (80 mL), extracted with ethyl acetate (50mL×3), and the combined organic phases were washed with a saturatedsolution of ammonium chloride (60 mL), dried over anhydrous sodiumsulfate (5 g) and concentrated to give 2A. ¹HNMR (400 MHz, deuteratedchloroform) δ=4.22-4.13 (m, 2H), 3.81 (br. s., 1H), 3.71 (t, J=6.1 Hz,2H), 3.19 (br. s., 2H), 2.45 (s, 2H), 1.70-1.61 (m, 2H), 1.51 (br. s.,2H), 1.44 (s, 9H), 1.27 (t, J=7.2 Hz, 3H).

Compound 2B

Compound 2A(5.00 g, 17.40 mmol) was dissolved in methanol (15.00 mL) at25° C., added with sodium hydroxide solution (4 M, 17.40 mL) understirring and stirred for 3 hours. TLC showed that the reaction wasmostly complete. The reaction solution was concentrated, extracted withethyl acetate (20 mL×2) to give the aqueous phase, which was adjusted topH=6 with a hydrochloric acid solution (6 N, 20 mL), and extracted withethyl acetate (20 mL×3). The combined organic phases were washed with asaturated solution of sodium chloride (25 mL), dried over anhydroussodium sulfate (2 g), and concentrated to give compound 2B. ¹H NMR (400MHz, deuterated chloroform) δ=3.95-3.69 (m, 2H), 3.20 (br. s., 2H), 2.52(s, 2H), 1.72 (d, J=12.8 Hz, 2H), 1.60-1.49 (m, 2H), 1.48-1.38 (m, 9H).

Compound 2C

Compound 2B (2 g, 7.71 mmol) and diphenylphosphoryl azide (2.76 g, 10.02mmol) were dissolved in toluene (30 mL), under nitrogen protection,added with triethylamine (10.95 g, 108.25 mmol), and stirred at 105° C.for 12 hours. TLC showed that the reaction was complete. The reactionsolution was quenched with a saturated solution of sodium bicarbonate(30 mL), and extracted with ethyl acetate (20 mL×2). The combinedorganic phases were washed with a saturated solution of ammoniumchloride (30 mL×3), dried over anhydrous sodium sulfate (2 g),concentrated, added with ethyl acetate (10 mL) under stirring, and thenadded with petroleum ether (30 mL) to precipitate a solid. The solid wasfiltered, and the filter cake was washed with petroleum ether (30 mL)and dried under vacuum to give compound 2C. ¹H NMR (400 MHz, deuteratedchloroform) δ=5.74 (br. s., 1H), 3.82 (br. s., 2H), 3.34-3.16 (m, 4H),1.93 (d, J=13.3 Hz, 2H), 1.71-1.61 (m, 2H), 1.46 (s, 9H).

Compound 2D

N4-(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4,6-diamine (100.00 mg,304.33 mmol) and isoamyl nitrite (71.31 mg, 608.67 mmol) were dissolvedin acetonitrile (3.00 mL), then added with copper bromide (135.95 mg,608.67 mmol), and stirred under nitrogen protection at 65° C. for 10hours. The target compound was detected by liquid chromatography massspectrometry and TLC showed that the raw materials were not completelyconsumed. The reaction mixture was filtered with DCM:MeOH=10:1 (22 mL),then concentrated, separated and purified by TLC (DCM:MeOH=12:1) to givecompound 2D finally. ¹H NMR (400 MHz, METHANOL-d4) δ=8.71 (s, 1H), 8.53(br. s., 1H), 8.05 (d, J=4.5 Hz, 1H), 7.75-7.64 (m, 1H), 7.32-7.19 (m,2H), 4.05 (s, 3H). LCMS (ESI) (5-95AB): m/z: 382.1 [M+1].

Compound 2E

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-formic acidtert-butyl ester, and6-bromo-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine wasreplaced with6-bromo-N-(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4-amine to givecompound 2E. LCMS (ESI) (10-80CD): m/z: 558.2 [M+1].

Compound 2F

According to the preparation method of compound 1J,4-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester was replaced with3-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylicacid tert-butyl ester to give compound 2F. The crude product would beused directly for the next step. LCMS (ESI) (5-95AB): m/z: 458.2 [M+1].

Compound 2

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with3-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decane-2-oneto give compound 2. The purity was verified by high performance liquidchromatography and liquid chromatography mass spectrometrysimultaneously. ¹H NMR (400 MHz, METHANOL-d4)=8.61-8.55 (m, 1H), 8.45(s, 1H), 8.04 (dd, J=2.2, 6.5 Hz, 1H), 7.79-7.56 (m, 1H), 7.45-7.02 (m,2H), 4.06 (s, 3H), 3.96 (s, 2H), 3.26 (d, J=11.0 Hz, 4H), 2.83 (s, 3H),2.46-2.17 (m, 4H). LCMS (ESI) (5-95AB): m/z: 472.2 [M+1].

Example 3 Compound 3A

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-formic acidtert-butyl ester to give compound 3A. ¹H NMR (400 MHz, DMSO-d₆)=8.72(br. s., 1H), 8.44 (br. s., 1H), 7.58 (br. s., 1H), 7.47 (br. s., 2H),7.31 (s, 2H), 3.98 (s, 3H), 3.82 (s, 2H), 3.63-3.50 (m, 4H), 1.87-1.69(m, 4H), 1.41 (s, 9H). LCMS (ESI) (5-95AB): m/z: 558.2 [M+1].

Compound 3B

According to the preparation method of compound 1J,4-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester was replaced with3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylicacid tert-butyl ester to give compound 3B. The crude product would beused directly for the next step. ¹H NMR (400 MHz, METHANOL-d4)=8.77 (s,1H), 8.71 (s, 1H), 7.58-7.50 (m, 2H), 7.46 (s, 1H), 7.30 (dt, J=1.2, 8.1Hz, 1H), 4.15 (s, 3H), 4.01 (s, 2H), 3.43-3.36 (m, 4H), 2.29-2.15 (m,4H). LCMS (ESI) (5-95AB): m/z: 458.3 [M+1].

Example 3 Compound 3

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decane-2-oneto give compound 3. The purity was verified by high performance liquidchromatography and liquid chromatography mass spectrometrysimultaneously. ¹H NMR (400 MHz, METHANOL-d4)=8.46 (br. s., 1H), 8.41(s, 1H), 7.61-7.53 (m, 1H), 7.46-7.37 (m, 1H), 7.32 (s, 1H), 7.23 (dt,J=1.2, 8.1 Hz, 1H), 4.06 (s, 3H), 3.94 (s, 2H), 3.35-3.32 (m, 2H),3.25-3.17 (m, 2H), 2.80 (s, 3H), 2.38-2.30 (m, 2H), 2.26-2.16 (m, 2H).LCMS (ESI) (5-95AB): m/z: 472.1 [M+1].

Example 4 Compound 4A

According to the preparation method of compound 1D,3-chloro-2-fluoroaniline was replaced with 3-chloro-2-methoxyaniline togive compound 4A. ¹H NMR (400 MHz, DMSO-d6) δ=9.76 (s, 1H), 8.89 (s,1H), 8.44 (s, 1H), 7.48 (dd, J=1.4, 8.0 Hz, 1H), 7.41 (dd, J=1.5, 8.2Hz, 1H), 7.31 (s, 1H), 7.23-7.14 (m, 1H), 4.02 (s, 3H), 3.67 (s, 3H).LCMS (ESI) (5-95AB): m/z: 394.0 [M+1].

Compound 4B

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-formic acidtert-butyl ester, and6-bromo-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine wasreplaced with6-bromo-N-(3-chloro-2-methoxyphenyl)-7-methoxyquinazolin-4-amine to givecompound 4B. ¹HNMR (400 MHz, METHANOL-d4) δ=8.44 (br. s., 2H), 7.70 (d,J=7.0 Hz, 1H), 7.34 (dd, J=1.4, 8.0 Hz, 2H), 7.17 (t, J=8.1 Hz, 1H),4.59 (s, 2H), 4.05 (s, 3H), 3.89 (s, 2H), 3.88-3.82 (m, 2H), 3.79 (s,3H), 2.08 (d, J=13.7 Hz, 2H), 1.95-1.87 (m, 2H), 1.49 (s, 9H). LCMS(ESI) (5-95AB): m/z: 570.4 [M+1].

Compound 4C

According to the preparation method of compound 1J,4-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester was replaced with3-(4-((3-chloro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylicacid tert-butyl ester to give compound 4C. The crude product would beused directly for the next step. ¹H NMR (400 MHz, METHANOL-d4)=8.73 (s,1H), 8.67 (s, 1H), 7.50 (ddd, J=1.5, 6.8, 8.2 Hz, 2H), 7.40 (s, 1H),7.24 (t, J=8.1 Hz, 1H), 4.15 (s, 3H), 4.00 (s, 2H), 3.80 (s, 3H),3.49-3.38 (m, 4H), 2.42-2.33 (m, 2H), 2.25-2.17 (m, 2H). LCMS (ESI)(5-95AB): m/z: 470.1 [M+1].

Compound 4

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with3-(4-((3-chloro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decane-2-oneto give compound 4. The purity was verified by high performance liquidchromatography and liquid chromatography mass spectrometrysimultaneously. ¹H NMR (400 MHz, METHANOL-d4) δ=8.46 (br s, 2H), 7.72(d, J=7.9 Hz, 1H), 7.42-7.28 (m, 2H), 7.21-7.14 (m, 1H), 4.06 (s, 3H),3.94 (s, 2H), 3.79 (s, 3H), 3.26-3.07 (m, 4H), 2.73 (s, 3H), 2.38-2.26(m, 2H), 2.24-2.10 (m, 2H). LCMS (ESI) (5-95AB): m/z: 484.1 [M+1].

Example 5 Compound 5

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with3-(4-((3-chloro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decane-2-one,and polyformaldehyde was replaced with acetone to give compound 5. Thepurity was verified by high performance liquid chromatography and liquidchromatography mass spectrometry simultaneously. 1H NMR (400 MHz,METHANOL-d4) δ=8.45 (s, 1H), 8.41 (s, 1H), 7.62-7.54 (m, 1H), 7.40 (dt,J=1.4, 7.4 Hz, 1H), 7.32 (s, 1H), 7.22 (dt, J=1.4, 8.1 Hz, 1H), 4.06 (s,3H), 3.95 (s, 2H), 3.59-3.51 (m, 1H), 3.50-3.40 (m, 2H), 3.40-3.32 (m,2H), 2.48-2.36 (m, 2H), 2.34-2.22 (m, 2H), 1.39 (d, J=6.5 Hz, 6H). LCMS(ESI) (5-95AB): m/z: 500.1 [M+1].

Example 6 Compound 6A

According to the preparation method of compound 1D,3-chloro-2-fluoroaniline was replaced with 3,4-dichloro-2-fluoroanilineto give compound 6A. ¹H NMR (400 MHz, METHANOL-d4) δ=8.65 (s, 1H), 8.46(s, 1H), 7.59 (t, J=8.2 Hz, 1H), 7.44 (dd, J=1.7, 8.8 Hz, 1H), 7.26 (s,1H), 4.06 (s, 3H). LCMS (ESI) (5-95AB): m/z: 415.9 [M+1].

Compound 6B

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-formic acidtert-butyl ester, and6-bromo-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine wasreplaced with6-bromo-N-(3,4-dichloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine togive compound 6B. LCMS (ESI) (5-95AB): m/z: 592.0 [M+1].

Compound 6C

According to the preparation method of compound 1J,4-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester was replaced with3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylicacid tert-butyl ester to give compound 6C. The crude product would beused directly for the next step. LCMS (ESI) (5-95AB): m/z: 492.0 [M+1].

Compound 6

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decane-2-oneto give compound 6. The purity was verified by high performance liquidchromatography and liquid chromatography mass spectrometrysimultaneously. ¹H NMR (400 MHz, METHANOL-d4) δ=8.47 (s, 1H), 8.39 (s,1H), 7.61 (br t, J=8.3 Hz, 1H), 7.44 (dd, J=1.9, 8.8 Hz, 1H), 7.33 (s,1H), 4.06 (s, 3H), 3.93 (s, 2H), 3.28-3.10 (m, 4H), 2.75 (s, 3H),2.34-2.14 (m, 4H). LCMS (ESI) (5-95AB): m/z: 506.1 [M+1].

Example 7 Compound 7A

4-oxypiperidine-1-formic acid tert-butyl ester (10.00 g, 50.19 mmol) andethyl 2-(diethoxyphosphoryl)acetate (11.25 g, 50.19 mmol) were dissolvedin N, N-dimethylformamide (50.00 mL), then added with potassiumcarbonate (13.87 g, 100.38 mmol) and stirred under nitrogen protectionat 80° C. for 2 hours. TLC showed that the reaction was complete. Thereaction mixture was added with water (600 mL), extracted with ethylacetate (100 mL×2), washed with saturated brine (100 mL×2), dried overanhydrous sodium sulfate (15 g), concentrated, separated and purified bycolumn chromatography (PE:EA=20:1, 10:1) to give compound 7A. ¹HNMR (400MHz, deuterated chloroform) δ ppm 5.71 (s, 1 H), 4.16 (q, J=7.15 Hz, 2H), 3.49 (dt, J=11.14, 5.79 Hz, 4 H), 2.94 (t, J=5.58 Hz, 2 H), 2.28 (t,J=5.65 Hz, 2 H), 1.47 (s, 9 H), 1.28 (t, J=7.09 Hz, 3 H).

Compound 7B

Potassium carbonate (256.57 mg, 1.86 mmol) and dimethyl sulfoxide (6 mL)were added to a 50 mL round-bottom flask, and the mixture was stirredand heated to 80° C. Compound 7A (1.00 g, 3.71 mmol) was then added andnitromethane (1.13 g, 18.56 mmol, 1.00 mL) was added slowly. Thereaction mixture was stirred under nitrogen protection at 80° C. for 2hours. TLC showed that the reaction was complete. The reaction liquidwas cooled down to 28° C., poured into 100 mL water and extracted withethyl acetate (30 mL×2). The organic phase was washed with saturatedsodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate(5.0 g), and concentrated to give compound 7B.

Compound 7C

The compound 4-(2-ethoxy-2-oxo-ethyl)-4-(nitromethyl)piperidine-1-formic acid tert-butyl ester (1.10 g, 3.15 mmol) wasdissolved in methanol (10.00 mL). Raney nickel (1.00 g) was added to thesolution, and after the removal of oxygen by vacuum, the gas in thereactor was displaced with hydrogen gas several times. The reactionliquid was stirred under hydrogen atmosphere (50 Psi) at 40° C. for 24hours. TLC showed that the reaction was complete. The reaction solutionwas filtered through Celite, concentrated, separated and purified bycolumn chromatography (silica gel, DCM:MeOH=10:1) to give compound 7C.¹H NMR (400 MHz, deuterated chloroform) δ ppm 5.78 (br s, 1 H), 3.49-3.6(m, 2 H), 3.26-3.38 (m, 2 H), 3.21 (s, 2 H), 2.24 (s, 2 H), 1.58-1.65(m, 4 H), 1.46 (s, 9 H).

Compound 7D

According to the preparation method of compound 11,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 3-oxo-2,8-diazaspiro[4.5]decane-8-formic acidtert-butyl ester, and6-bromo-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine wasreplaced with6-bromo-N-(3,4-dichloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine togive compound 7D. ¹H NMR(400 MHz, deuterated chloroform) δ ppm 8.63 (brs, 1 H), 8.18 (br s, 1 H), 8.10 (br s, 1 H), 7.94 (br s, 1 H), 7.15 (brs, 1 H), 3.88 (s, 3 H), 3.71 (s, 2 H), 3.50 (br s, 4 H), 2.54 (s, 2 H),1.49 (s, 9 H), 1.42-1.47 (m, 4 H). LCMS (ESI) (5-95AB): m/z: 590.1[M+1].

Compound 7E

According to the preparation method of compound 1J,4-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester was replaced with2-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylicacid tert-butyl ester to give compound 7E. The crude product would beused directly for the next step. LCMS (ESI) (5-95AB): m/z: 490.1 [M+1].

Compound 7

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with2-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2,8-diazaspiro[4.5]decane-2-oneto give compound 7. The purity was verified by high performance liquidchromatography and liquid chromatography mass spectrometrysimultaneously. ¹H NMR (400 MHz, METHANOL-d4) δ ppm 8.46 (br s, 3 H),8.30 (s, 1 H), 7.61 (br t, J=8.16 Hz, 1 H), 7.45 (dd, J=8.85, 1.82 Hz, 1H), 7.33 (s, 1 H), 4.03 (s, 3H), 3.80 (s, 2 H), 3.15-3.29 (m, 3 H), 2.84(s, 3 H), 2.57-2.69 (m, 2 H), 2.08 (br s, 4 H). LCMS (ESI) (5-95AB):m/z: 504.0 [M+1].

Example 8 Compound 8A

Ethyl 4-piperidinecarboxylate (5.00 g, 31.80 mmol) anddiisopropylethylamine (8.22 g, 63.60 mmol) were dissolved intetrahydrofuran (50.00 mL), then added with Boc₂O (6.94 g, 31.80mmol)and stirred under nitrogen protection at 30° C. for 5 hours. TLCshowed that the reaction was complete. After the reaction solution wasconcentrated, dichloride methane (30 mL) was added and washed twice withpotassium carbonate solution (15 mL). The organic phase was dried overanhydrous sodium sulfate (1 g), concentrated, separated and purified bycolumn chromatography (DCM:MeOH=20:1 to 10:1) to give compound 8A. ¹HNMR (400 MHz, deuterated chloroform) δ=4.14 (q, J=7.1 Hz, 2H), 4.02 (d,J=8.9 Hz, 2H), 2.83 (t, J=11.7 Hz, 2H), 2.47-2.39 (m, 1H), 1.87 (d,J=10.9 Hz, 2H), 1.69-1.59 (m, 2H), 1.46 (s, 9H), 1.26 (t, J=7.2 Hz, 3H).

Compound 8B

O1-tert-butyl O4-ethyl piperidine-1,4-dicarboxylate (4.00 g, 15.54 mmol)was dissolved in tetrahydrofuran (20 mL), then added with lithiumdiisopropylamide (2 M, 10.88 mL) under nitrogen protection at −65° C.,and stirred at −65° C. for 1.5 hours. Then bromoacetonitrile (2.80 g,23.32 mmol) diluted with tetrahydrofuran (5 mL) was added to thereaction solution, and the reaction mixture was stirred at −65° C. for1.5 hours. Then the reaction mixture was stirred at 20° C. for 12 hours.TLC showed that new products appeared but the raw materials were notcompletely consumed. Ammonium chloride solution (50 mL) was added to thereaction solution and extracted four times with ethyl acetate (50 mL).The combined organic phases were dried over anhydrous sodium sulfate (3g), concentrated, separated and purified by column chromatography(PE:EA=10:1 to 3:1) to give compound 8B. ¹HNMR (400 MHz, deuteratedchloroform) δ=4.26 (d, J=7.1 Hz, 2H), 3.83 (d, J=10.8 Hz, 2H), 3.08 (br.s., 2H), 2.60 (s, 2H), 2.23-2.11 (m, 2H), 1.60-1.52 (m, 2H), 1.46 (s,9H), 1.32 (t, J=7.2 Hz, 3H).

Compound 8C

4-(Cyanomethyl)piperidine-1,4-dicarboxylic acid O1-tert-butyl O4-ethylester (1.80 g, 6.07 mmol) and ammonia water (2.00 mL) were dissolved inmethanol (40.00 mL), then added with Raney nickel (1.80 g) in nitrogenatmosphere. The reaction system was vacuumed, displaced with nitrogengas three times and with hydrogen gas three times. The reaction mixturewas stirred under hydrogen atmosphere (50 psi) at 60° C. for 15 hours.TLC showed that new products appeared and the raw materials werecompletely consumed. The reaction solution was filtered with methanol(20 mL), concentrated, added with water (20 mL) and extracted with ethylacetate (25 mL) three times. The combined organic phases were dried overanhydrous sodium sulfate (1 g) and concentrated to give compound 8C.¹HNMR (400 MHz, deuterated chloroform) δ=6.01 (br s, 1H), 3.99 (br s,2H), 3.35 (t, J=6.8 Hz, 2H), 2.99 (br t, J=11.3 Hz, 2H), 2.13-2.01 (m,2H), 1.91-1.79 (m, 2H), 1.46 (s, 11H).

Compound 8D

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 1-oxo-2,8-diazaspiro[4.5]decane-8-formic acidtert-butyl ester, and6-bromo-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine wasreplaced with6-bromo-N-(3,4-dichloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine togive compound 8D. The crude produce would be used directly for the nextstep. LCMS (ESI) (5-95AB): m/z: 590.1 [M+1].

Compound 8E

According to the preparation method of compound 1J,4-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester was replaced with2-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylicacid tert-butyl ester to give compound 8E. The crude product would beused directly for the next step. LCMS (ESI) (5-95AB): m/z: 490.0 [M+1].

Compound 8

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with2-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2,8-diazaspiro[4.5]decane-2-oneto give compound 8. The purity was verified by high performance liquidchromatography and liquid chromatography mass spectrometrysimultaneously. ¹H NMR (400 MHz, METHANOL-d4) δ=8.47 (br s, 1H), 8.30(s, 1H), 7.61 (br t, J=8.0 Hz, 1H), 7.45 (dd, J=1.9, 8.8 Hz, 1H), 7.33(s, 1H), 4.02 (s, 3H), 3.87 (t, J=6.9 Hz, 2H), 3.53 (br dd, J=4.3, 11.6Hz, 2H), 3.23-3.10 (m, 2H), 2.86 (s, 3H), 2.34-2.17 (m, 4H), 1.97 (br d,J=15.1 Hz, 2H). LCMS (ESI) (5-95AB): m/z: 504.1 [M+1].

Example 9 Compound 9A

According to the preparation method of compound 1D,3-chloro-2-fluoroaniline was replaced with 4-bromo-2-fluoroaniline togive 9A. ¹HNMR (400 MHz, METHANOL-d4) δ=8.62 (s, 1H), 8.43 (s, 1H), 7.59(t, J=8.3 Hz, 1H), 7.51-7.38 (m, 2H), 7.22 (s, 1H), 4.05 (s, 3H). LCMS(ESI) (5-95AB): m/z: 425.9 [M+1].

Compound 9B

According to the preparation method of compound 11,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-formic acidtert-butyl ester, and6-bromo-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine wasreplaced with6-bromo-N-(4-bromo-2-fluorophenyl)-7-methoxyquinazolin-4-amine to givecompound 9B. LCMS (ESI) (5-95AB): m/z: 602.1 [M+1].

Compound 9C

According to the preparation method of compound 1J,4-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester was replaced with3-(4-((4-bromo-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylicacid tert-butyl ester to give compound 9C. The crude product would beused directly for the next step. LCMS (ESI) (10-80CD): m/z: 502.1[M+1].

Compound 9

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with3-(4-((4-bromo-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decane-2-oneto give compound 9. The purity was verified by high performance liquidchromatography and liquid chromatography mass spectrometrysimultaneously. ¹H NMR (400 MHz, METHANOL-d4) δ=8.45 (s, 1H), 8.39 (s,1H), 7.61 (t, J=8.3 Hz, 1H), 7.50-7.41 (m, 2H), 7.32 (s, 1H), 4.06 (s,3H), 3.93 (s, 2H), 3.20 (br s, 2H), 3.14-3.07 (m, 2H), 2.73 (s, 3H),2.35-2.26 (m, 2H), 2.22-2.11 (m, 2H). LCMS (ESI) (5-95AB): m/z: 516.0[M+1].

Example 10 Compound 10A

According to the preparation method of compound 1D,3-chloro-2-fluoroaniline was replaced with 3-chloro-2,4-difluoroanilineto give compound 10A. ¹H NMR (400 MHz, METHANOL-d4) δ=8.63 (s, 1H), 8.43(s, 1H), 7.54 (dt, J=5.6, 8.6 Hz, 1H), 7.25 (s, 1H), 7.20 (dt, J=2.0,8.8 Hz, 1H), 4.06 (s, 3H). LCMS (ESI) (5-95AB): m/z: 399.9 [M+1].

Compound 10B

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 3-oxo-3,8-diazaspiro[4.5]decane-8-formic acidtert-butyl ester, and6-bromo-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine wasreplaced with6-bromo-N-(3-chloro-2,4-difluorophenyl)-7-methoxyquinazolin-4-amine togive compound 10B. ¹H NMR (400 MHz, METHANOL-d4) δ=8.43 (br s, 1H), 8.38(s, 1H), 7.59-7.49 (m, 1H), 7.31 (s, 1H), 7.25-7.16 (m, 1H), 4.06 (s,3H), 3.88 (s, 2H), 2.07 (br d, J=13.6 Hz, 2H), 1.97-1.85 (m, 4H),1.81-1.67 (m, 2H), 1.48 (s, 9H).

Compound 10C

According to the preparation method of compound 1J,4-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester was replaced with2-(4-((3-chloro-2,4-difluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylicacid tert-butyl ester to give compound 10C. The crude product would beused directly for the next step. ¹HNMR (400 MHz, METHANOL-d4) δ=8.79 (brs, 1H), 8.64 (s, 1H), 7.62-7.52 (m, 1H), 7.43 (s, 1H), 7.29 (dt, J=1.9,8.8 Hz, 1H), 4.15 (s, 3H), 4.00 (s, 2H), 2.37 (br d, J=14.1 Hz, 2H),2.28-2.15 (m, 4H), 2.05-1.96 (m, 2H). LCMS (ESI) (5-95AB): m/z: 475.9[M+1].

Compound 10

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with2-(4-((3-chloro-2,4-difluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2,8-diazaspiro[4.5]decane-3-oneto give compound 10. The purity was verified by high performance liquidchromatography and liquid chromatography mass spectrometrysimultaneously. ¹H NMR (400 MHz, METHANOL-d4) δ=8.46 (br s, 1H), 8.40(s, 1H), 7.54 (dt, J=5.7, 8.6 Hz, 1H), 7.33 (br s, 1H), 7.20 (dt, J=1.9,8.8 Hz, 1H), 4.06 (s, 3H), 3.93 (s, 2H), 3.26 (br s, 2H), 3.20-3.12 (m,2H), 2.76 (s, 3H), 2.37-2.27 (m, 2H), 2.26-2.15 (m, 2H). LCMS (ESI)(5-95AB): m/z: 490.0 [M+1].

Example 11 Compound 11A

Acetonitrile (2.06 g, 50.18 mmol) was added to tetrahydrofuran (30.00mL); added dropwise with n-butyl lithium (2.5 M, 20.07 mL) at −78° C.and under nitrogen protection,and stirred at −78° C. for 1 hour.4-oxoperidine-1-formic acid tert-butyl ester (5.00 g, 25.09 mmol) wasadded to the reaction solution under nitrogen protection at −78-25° C.,and the reaction mixture was stirred at −78-25° C. for 9 hours. TLCshowed that new products appeared but the raw materials were notcompletely consumed. The reaction solution was concentrated, added withethyl acetate (10 mL) and water (20 mL), and then extracted with ethylacetate (20 mL) three times. The combined organic phases were dried overanhydrous sodium sulfate (5 g), concentrated, separated and purified bycolumn chromatography (PE:EA=5:1 to 2:1) to give compound 11A. ¹H NMR(400 MHz, deuterated chloroform) δ=3.91 (br s, 2H), 3.15 (br t, J=11.6Hz, 2H), 2.54 (s, 2H), 1.77-1.70 (m, 2H), 1.67-1.60 (m, 2H), 1.46 (s,9H).

Compound 11B

4-(Cyanomethyl)-4-hydroxy-piperidine-1-formic acid tert-butyl ester(800.00 mg, 3.33 mmol) was dissolved in methanol (20 mL), added withBoc₂O (2.91 g, 13.32 mmol) and then added with Raney nickel (0.1 g). Thereaction system was vacuumed, displaced with nitrogen gas three timesand with hydrogen gas three times. The reaction mixture was stirredunder hydrogen atmosphere (50 psi) at 40° C. for 10 hours. TLC showedthat new products appeared and the raw materials were completelyconsumed. The reaction solution was filtered with methanol (20 mL),concentrated, separated and purified by column chromatography (PE:EA=5:1to 2:1) to give compound 11B. ¹H NMR (400 MHz, deuterated chloroform)δ=4.92 (br s, 1H), 3.79 (br s, 2H), 3.30 (q, J=6.4 Hz, 2H), 3.18 (br t,J=11.4 Hz, 2H), 1.65-1.57 (m, 4H), 1.52 (br dd, J=4.4, 11.4 Hz, 2H),1.44 (s, 9H).

Compound 11C

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 2-oxo-1-oxa-3,9-diazaspiro[5.5]undecane-9-formic acidtert-butyl ester to give compound 11C. ¹H NMR (400 MHz, METHANOL-d4)δ=8.46 (br s, 1H), 8.36 (br s, 1H), 7.59 (br s, 1H), 7.40 (br t, J=7.2Hz, 1H), 7.31 (br s, 1H), 7.22 (br t, J=7.8 Hz, 1H), 4.03 (s, 3H), 3.95(br d, J=13.3 Hz, 2H), 3.88-3.82 (m, 2H), 3.77-3.70 (m, 2H), 1.89-1.82(m, 4H), 1.68-1.61 (m, 2H), 1.46 (s, 9H). LCMS (ESI) (5-95AB): m/z:572.1 [M+1].

Compound 11D

According to the preparation method of compound 1J,4-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester was replaced with3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxo-1-oxa-3,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester to give compound 11D. The crude product would beused directly for the next step. ¹H NMR (400 MHz, METHANOL-d4) δ=8.78(br s, 1H), 8.70 (br s, 1H), 7.51 (br t, J=7.0 Hz, 3H), 7.32-7.23 (m,1H), 4.10 (s, 3H), 3.78 (br t, J=5.6 Hz, 2H), 3.44 (br s, 2H), 2.29 (brd, J=7.5 Hz, 2H), 2.18-2.08 (m, 4H), 1.95 (br t, J=6.1 Hz, 2H). LCMS(ESI) (5-95AB): m/z: 472.1 [M+1].

Compound 11

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-1-oxa-3,9-diazaspiro[4.5]undecane-2-oneto give compound 11. The purity was verified by high performance liquidchromatography and liquid chromatography mass spectrometrysimultaneously. ¹HNMR (400 MHz, METHANOL-d4) δ=8.46 (s, 1H), 8.36 (s,1H), 7.64-7.54 (m, 1H), 7.41 (ddd, J=1.6, 6.7, 8.2 Hz, 1H), 7.33 (s,1H), 7.27-7.19 (m, 1H), 4.03 (s, 3H), 3.76 (br s, 2H), 3.40 (br s, 2H),3.30-3.17 (m, 2H), 2.86 (s, 3H), 2.26 (br s, 4H), 2.19-2.06 (m, 2H).LCMS (ESI) (5-95AB): m/z: 486.1 [M+1].

Example 12 Compound 12A

According to the preparation method of compound 1B,2-amino-5-bromo-4-methoxybenzoic acid was replaced with2-amino-5-bromo-benzoic acid to give compound 12A. ¹H NMR (400 MHz,DMSO-d6) δ=8.19 (d, J=2.3 Hz, 1H), 8.15-8.11 (s, 1H), 7.95 (dd, J=2.4,8.7 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H).

Compound 12B

According to the preparation method of compound 1C,6-bromo-7-methoxyquinazolin-4-ol was replaced with6-bromo-quinazolin-4-ol to give compound 12B. The crude product would beused directly for the next step. LCMS (ESI) (5-95AB): m/z: 242.9 [M+1].

Compound 12C

According to the preparation method of compound 1D,6-bromo-4-chloro-7-methoxyquinazoline was replaced with6-bromo-4-chloroquinazoline to give 12C. ¹H NMR (400 MHz, METHANOL-d4)δ=8.62 (d, J=2.0 Hz, 1H), 8.51 (s, 1H), 8.00 (dd, J=2.1, 8.9 Hz, 1H),7.74 (d, J=8.9 Hz, 1H), 7.62-7.52 (m, 1H), 7.47-7.39 (m, 1H), 7.28-7.21(m, 1H). LCMS (ESI) (5-95AB): m/z: 351.9.

Compound 12D

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-formic acidtert-butyl ester, and6-bromo-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine wasreplaced with 6-bromo-N-(3-chloro-2,4-difluorophenyl)quinazolin-4-amineto give compound 12D. ¹H NMR (400 MHz, METHANOL-d4) δ=8.50-8.34 (m, 2H),8.14 (d, J=1.8 Hz, 1H), 7.79 (br d, J=9.2 Hz, 1H), 7.59 (br s, 1H), 7.40(br t, J=7.2 Hz, 1H), 7.28-7.19 (m, 1H), 4.04 (s, 2H), 3.83-3.73 (m,4H), 1.92-1.86 (m, 4H), 1.48 (s, 9H). LCMS (ESI) (5-95AB): m/z: 528.1[M+1].

Compound 12E

According to the preparation method of compound 1J,4-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester was replaced with3-(4-((3-chloro-2-fluorophenyl)amino)-quinazolin-6-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylicacid tert-butyl ester to give compound 12E. The crude product would beused directly for the next step. ¹H NMR (400 MHz, METHANOL-d4) δ=8.81(s, 1H), 8.76 (dd, J=2.4, 9.3 Hz, 1H), 8.50 (d, J=2.3 Hz, 1H), 7.99 (d,J=9.3 Hz, 1H), 7.58 (dddd, J=1.6, 6.7, 8.1, 16.0 Hz, 2H), 7.35 (dt,J=1.4, 8.1 Hz, 1H), 4.19 (s, 2H), 3.42-3.37 (m, 4H), 2.28-2.19 (m, 4H).LCMS (ESI) (5-95AB): m/z: 428.1 [M+1].

Compound 12

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with3-(4-((3-chloro-2-fluorophenyl)amino)-quinazolin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decane-2-oneto give compound 12. The purity was verified by high performance liquidchromatography and liquid chromatography mass spectrometrysimultaneously. ¹H NMR (400 MHz, METHANOL-d4) δ=8.43 (s, 1H), 8.41 (brd, J=2.3 Hz, 1H), 8.18 (d, J=2.2 Hz, 1H), 7.83 (d, J=9.2 Hz, 1H),7.62-7.53 (m, 1H), 7.47-7.37 (m, 1H), 7.24 (dt, J=1.2, 8.1 Hz, 1H), 4.12(s, 2H), 3.40 (br d, J=12.0 Hz, 2H), 3.30-3.18 (m, 2H), 2.85 (s, 3H),2.37-2.17 (m, 4H). LCMS (ESI) (5-95AB): m/z: 442.1 [M+1].

Example 13 Compound 13A

3-Oxoazetidin-1-carboxylic acid tert-butyl ester (9.00 g, 52.57 mmol)was dissolved in ethanol (30.00 mL) at 20° C., and added withnitromethane (33.90 g, 555.37 mmol) and triethylamine (730.00 mg, 7.21mmol). The mixture was stirred at 20° C. for 16 hours. TLC (PE:EA=5:1)showed that the reaction was complete. The reaction mixture wasconcentrated under vacuum to give compound 13A. ¹HNMR (400 MHz, DMSO-d6)δ=6.44 (s, 1H), 4.86 (s, 2H), 4.04 (br d, J=8.9 Hz, 2H), 3.74 (br d,J=9.2 Hz, 2H), 1.38 (s, 9H).

Compound 13B

3-Hydroxy-3-(nitromethyl)azetidin-1-carboxylic acid tert-butyl ester(6.00 g, 25.84 mmol) was dissolved in methanol (60.00 mL) at 20° C., andadded with wet palladium on carbon (10%, 0.6 g) under nitrogenprotection. The suspension was degassed, displaced,and purified withhydrogen gas four times, and then stirred under hydrogen atmosphere (15psi) at 20° C. for 16 hours. TLC (petroleum ether: ethyl acetate=): 1)showed that the reaction was complete. The reaction mixture was filteredand concentrated under vacuum to give compound 13B. ¹H NMR (400 MHz,DMSO-d6) δ=5.55 (br s, 1H), 3.87 (br d, J=7.9 Hz, 1H), 3.73 (br d, J=7.8Hz, 1H), 3.63-3.51 (m, 2H), 2.90 (s, 1H), 2.59 (s, 1H), 1.36 (s, 9H).

Compound 13C

3-(Aminomethyl)-3-hydroxy-azetidin-1-carboxylic acid tert-butyl ester(2.00 g, 9.89 mmol) was dissolved in dichloromethane (40.00 mL) at 20°C., added with triethylamine (3.00 g, 29.67 mmol) and triphosgene (3.23g, 10.88 mmol), and then stirred for 3 hours. TLC (DCM:MeOH=10:1) showedthat the reaction was complete. The reaction was quenched with saturatedammonium chloride solution (60 mL) and stirred for 10 minutes. Theaqueous phase was separated, and the organic phase was washed with water(2*60 mL). The combined water phases were extracted with dichloromethane(3*30 mL). The combined organic phases were dried over anhydrous sodiumsulfate (20 g), filtered and concentrated under vacuum. The residue wasseparated and purified by column chromatography (silica gel,dichloromethane/methanol=100/1 to 50/1) to give compound 13C. ¹H NMR(400 MHz, deuterated chloroform) δ=4.38-4.22 (m, 2H), 4.11-3.98 (m, 2H),3.84-3.58 (m, 2H), 1.68 (br s, 1H), 1.47 (s, 9H).

Compound 13D

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylicacid tert-butyl ester to give compound 13D. LCMS (ESI) (5-95AB):m/z:530.0 [M+1].

Compound 13E

According to the preparation method of compound 1J,4-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester was replaced with7-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylicacid tert-butyl ester to give compound 13E. The crude product would beused directly for the next step.

Compound 13

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with7-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-5-oxa-2,7-diazaspiro[3.4]octane-6-oneto give compound 13. The purity was verified by high performance liquidchromatography and liquid chromatography mass spectrometrysimultaneously. ¹H NMR (400 MHz, DMSO-d6) δ=9.91 (br s, 1H), 8.47 (s,2H), 8.21 (s, 1H), 7.49 (br t, J=7.2 Hz, 2H), 7.34 (s, 1H), 7.31-7.23(m, 1H), 4.19 (s, 2H), 3.99 (s, 3H), 3.55-3.54 (m, 2H), 3.40 (br d,J=8.8 Hz, 3H), 2.31 (s, 3H). LCMS (ESI) (5-95CD): m/z:444.0 [M+1].

Example 14 Compound 14A

According to the preparation method of compound 13A,3-oxoazetidin-1-carboxylic acid tert-butyl ester was replaced withtetrahydropyran-4-one to give compound 14A. ¹H NMR (400 MHz, deuteratedchloroform) δ ppm 4.45 (s, 2 H), 3.82 (t, J=2.6 Hz, 2 H), 3.80 (d, J=2.6Hz, 2 H), 2.76-3.20 (m, 1 H), 1.71-1.82 (m, 2 H), 1.59-1.67 (m, 2 H).

Compound 14B

According to the preparation method of compound 13B,3-hydroxy-3-(nitromethyl)azetidin-1-carboxylic acid tert-butyl ester wasreplaced with 4-(nitromethyl)tetrahydro-2H-pyran-4-ol to give compound14B. ¹H NMR (400 MHz, deuterated chloroform) δ ppm 3.75-3.82 (m, 4 H),3.48 (s, 1 H), 3.00 (s, 1 H), 2.63 (s, 2 H), 1.53-1.60 (m, 2 H),1.45-1.51 (m, 2 H).

Compound 14C

According to the preparation method of compound 13C,3-(aminomethyl)-3-hydroxy-azetidin-1-carboxylic acid tert-butyl esterwas replaced with 4-(aminomethyl)tetrahydro-2H-pyran-4-ol to givecompound 14C. ¹H NMR (400 MHz, deuterated chloroform) δ ppm 3.71-3.94(m, 7 H), 1.83-2.04 (m, 3 H), 1.83-2.04 (m, 1 H).

Compound 14

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 1,8-dioxa-3-azaspiro[4.5]decane-2-one to give compound14. ¹HNMR (400 MHz, deuterated chloroform) δ ppm 8.72 (s, 1 H),8.24-8.34 (m, 1 H), 8.06 (s, 1 H), 7.62 (br s, 1 H), 7.30 (s, 1 H),7.10-7.22 (m, 2 H), 4.00 (s, 3 H), 3.95 (br d, J=9.9 Hz, 2 H), 3.83-3.90(m, 4 H), 2.13 (br d, J=13.8 Hz, 2 H), 1.95-2.02 (m, 2 H). LCMS (ESI)(5-95AB):m/z: 459.0 [M+1].

Example 15 Compound 15A

According to the preparation method of compound 13A,3-oxoazetidin-1-carboxylic acid tert-butyl ester was replaced withoxetan-3-one to give title compound 15A. ¹HNMR (400 MHz, deuteratedchloroform) δ ppm 4.84 (s, 2 H), 4.73 (d, J=7.7 Hz, 2 H), 4.62 (d, J=8.1Hz, 2 H).

Compound 15B

According to the preparation method of compound 13B,3-hydroxy-3-(nitromethyl)azetidin-1-carboxylic acid tert-butyl ester wasreplaced with 3-(nitromethyl)oxetan-3-ol to give compound 15B. ¹H NMR(400 MHz, deuterated chloroform) δ ppm 4.65 (d, J=7.0 Hz, 2 H), 4.43 (d,J=7.3 Hz, 2 H), 3.09 (s, 2 H).

Compound 15C

According to the preparation method of compound 13C,3-(aminomethyl)-3-hydroxy-azetidin-1-carboxylic acid tert-butyl esterwas replaced with 3-(aminomethyl)oxetan-3-ol to give compound 15C. ¹HNMR (400 MHz, deuterated chloroform) δ ppm 4.99 (d, J=8.9 Hz, 2 H), 4.59(d, J=8.1 Hz, 2 H), 4.29 (s, 2 H).

Compound 15

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 2,5-dioxa-7-azaspiro[3.4]octane-6-one to give compound15. 1H NMR (400 MHz, deuterated chloroform) δ ppm 8.74 (s, 1 H),8.33-8.41 (m, 1 H), 8.01 (s, 1 H), 7.56 (br s, 1 H), 7.35 (s, 1 H),7.13-7.22 (m, 2 H), 5.15 (d, J=8.4 Hz, 2 H), 4.80 (d, J=8.3 Hz, 2 H),4.37 (s, 2 H), 4.03 (s, 3 H). LCMS (ESI) (5-95AB):m/z: 431.0 [M+1].

Example 16 Compound 16A

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-formic acidtert-butyl ester, and6-bromo-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine wasreplaced with 6-bromo-7-methoxyquinazolin-4-ol to give compound 16A. ¹HNMR (400 MHz, deuterated chloroform) δ ppm 8.23 (s, 1 H), 8.05 (s, 1 H),7.22 (s, 1 H), 3.99 (s, 3 H), 3.78-3.91 (m, 2 H), 3.73 (s, 2 H),3.33-3.41 (m, 2 H), 2.08 (br d, J=13.43 Hz, 2 H), 1.74-1.85 (m, 2 H),1.48 (s, 9 H). LCMS (ESI) (5-95AB): m/z: 431.3 [M+1].

Compound 16B

3-(4-Hydroxy-7-methoxy-quinazolin-6-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-formicacid tert-butyl ester (500.00 mg, 847.95 mmol) was dissolved inacetonitrile (10 mL), then added with BOP (450.04 mg, 1.02 mmol) and DBU(180.73 mg, 1.19 mmol), and reacted at 26° C. for 1 hour. LCMS showedthat the raw materials were completely consumed to obtain intermediates.Then DBU (180.73 mg, 1.19 mmol) and m-chlorophenol (163.52 mg, 1.27mmol) were added successively, and the reaction solution was stirred at26° C. for 1 hour. LCMS showed that the intermediates were completelyconsumed and the target compound was detected. The reaction mixture wasfiltered, concentrated, separated and purified by column chromatography(silica gel, PE/EA=1:1) to give compound 16B. ¹H NMR (400 MHz,deuterated chloroform) δ ppm 8.71 (s, 1 H), 8.32-8.39(m, 1 H),7.38-7.48(m,2H), 7.28-7.33(m,2H),7.16(ddd, J=8.16,2.20, 0.94 Hz, 1 H),4.06 (s, 3 H), 3.81 (s, 2 H), 3.24-3.48 (m, 4 H), 2.08-2.17 (m, 2 H),1.78-1.86 (m, 2 H), 1.49 (s, 9 H). LCMS (ESI) (5-95AB): m/z: 541.0[M+1].

Compound 16C

According to the preparation method of compound 1J,4-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester was replaced with3-(4-(3-chlorophenoxy)-7-methoxyquinazolin-6-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylicacid tert-butyl ester to give compound 16C. The crude product would beused directly for the next step. LCMS (ESI) (5-95AB): m/z: 441.3 [M+1].

Compound 16

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with3-(4-(3-chlorophenoxy)-7-methoxyquinazolin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decane-2-oneto give compound 16. The purity was verified by high performance liquidchromatography and liquid chromatography mass spectrometrysimultaneously. ¹H NMR (400 MHz, deuterated chloroform) δ ppm 8.71 (s, 1H), 8.35 (s, 1 H), 7.39-7.46 (m, 2 H), 7.28-7.33 (m, 2 H), 7.17 (dd,J=8.03, 1.25 Hz, 1 H), 4.06 (s, 3 H), 3.81 (s, 2 H), 2.61 (br s, 4 H),2.36 (s, 3 H), 2.17 (br d, J=13.43 Hz, 2 H), 1.87-2.01 (m, 2 H). LCMS(ESI) (5-95AB): m/z: 455.1 [M+1].

Example 17 Compound 17A

3-Oxoperidine-1,4-dicarboxylic acid 1-tert-butyl-4-ethyl ester (4.50 g,16.59 mmol) was dissolved in ethanol (30 mL), added with sodiumborohydride (313.73 mg, 8.30 mmol) in nitrogen atmosphere, and stirredat 30° C. for 1 hour. TLC showed that new products appeared and the rawmaterials were completely consumed. The reaction solution wasconcentrated, added with ethyl acetate (20 mL) and water (20 mL), andthen extracted with ethyl acetate (20 mL) three times. The combinedorganic phases were washed with brine (40 mL) one time, then dried overanhydrous sodium sulfate (1 g), concentrated, separated and purified bycolumn chromatography (PE:EA=10:1 to 3:1) to give compound 17A. ¹H NMR(400 MHz, deuterated chloroform) δ=4.26-3.99 (m, 5H), 2.97 (br s, 1H),2.90-2.78 (m, 1H), 2.60-2.48 (m, 1H), 2.11-2.03 (m, 1H), 1.79-1.67 (m,1H), 1.46 (s, 9H), 1.32-1.25 (m, 3H).

Compound 17B

3-Hydroxyperidine-1,4-dicarboxylic acid 1-tert-butyl-4-ethyl ester (3.3g, 12.07 mmol) was dissolved in methanol (20 mL), added with sodiumhydroxide solution (4 M, 12.07 mL) and stirred at 30° C. for 1 hour. TLCshowed that new products appeared and the raw materials were completelyconsumed. The reaction solution was concentrated, added with water (20mL) and washed with ethyl acetate (20 mL) three times. The obtainedaqueous phase was adjusted to be acidic with hydrochloric acid (2 M, 5mL), extracted with ethyl acetate (25 mL) three times. Then the combinedorganic phases were washed with brine (40 mL) three times, then driedover anhydrous sodium sulfate (1 g), concentrated to give compound 17B.¹H NMR (400 MHz, deuterated chloroform) δ=4.40-3.96 (m, 3H), 3.12-2.37(m, 3H), 2.09-1.97 (m, 3H), 1.83-1.56 (m, 1H), 1.48-1.44 (s, 9H).

Compound 17C

According to the preparation method of compound 2C,2-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl) acetic acid wasreplaced with 1-tert-butoxycarbonyl-3-hydroxypiperidine-4-carboxylicacid to give compound 17C. ¹H NMR (400 MHz, deuterated chloroform)δ=5.71 (br s, 1H), 4.16-4.05 (m, 1H), 3.96 (dd, J=4.1, 14.9 Hz, 1H),3.44 (br d, J=11.5 Hz, 2H), 3.35-3.13 (m, 1H), 2.82-2.75 (m, 1H),1.99-1.82 (m, 2H), 1.47 (s, 9H).

Compound 17D

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 2-oxo-hexahydrooxazo[5,4-c]pyridine-5(2H)-formic acidtert-butyl ester to give compound 17D. ¹H NMR (400 MHz, METHANOL-d4)δ=8.45 (br s, 1H), 8.37 (s, 1H), 7.61-7.50 (m, 1H), 7.41 (br t, J=7.2Hz, 1H), 7.32 (s, 1H), 7.27-7.20 (m, 1H), 4.05 (s, 3H), 4.01-3.81 (m,2H), 3.63 (s, 2H), 3.55-3.42 (m, 2H), 2.00-1.91 (m, 1H), 1.81-1.73 (m,1H), 1.45 (s, 9H). LCMS (ESI) (5-95AB): m/z: 544.3 [M+1].

Compound 17E

According to the preparation method of compound 1J,4-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester was replaced with1-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxo-hexahydrooxazo[5,4-c]pyridine-5(2H)-carboxylicacid tert-butyl ester to give compound 17E. The crude product would beused directly for the next step. ¹H NMR (400 MHz, METHANOL-d4) δ=8.78(s, 1H), 8.74 (s, 1H), 7.57-7.46 (m, 3H), 7.33-7.25 (m, 1H), 4.14 (s,3H), 3.77-3.43 (m, 6H), 2.23-2.13 (m, 1H), 1.91-1.70 (m, 1H). LCMS (ESI)(5-95AB): m/z: 444.2 [M+1].

Compound 17

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with1-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-hexahydrooxazo[5,4-c]pyridin-2(1H)-oneto give compound 17. The purity was verified by high performance liquidchromatography and liquid chromatography mass spectrometrysimultaneously. ¹H NMR (400 MHz, METHANOL-d4) δ=8.46 (s, 1H), 8.40 (s,1H), 8.21 (br s, 1H), 7.60-7.50 (m, 1H), 7.48-7.37 (m, 1H), 7.33 (s,1H), 7.27-7.15 (m, 1H), 5.11-4.94 (m, 1H), 4.65-4.51 (m, 1H), 4.05 (s,3H), 3.28-3.16 (m, 1H), 3.09 (dd, J=5.6, 13.1 Hz, 1H), 2.91-2.78 (m,1H), 2.76-2.65 (m, 1H), 2.59 (s, 3H), 2.06 (tdd, J=4.6, 9.5, 14.5 Hz,1H), 1.95-1.80 (m, 1H). LCMS (ESI) (5-95AB): m/z: 458.1 [M+1].

Example 18 Compound 18A

Triphosgene (9.77 g, 32.93 mmol, 1.00 eq.) and sodium bicarbonate (12.25g, 145.88 mmol, 5.67 mL, 4.43 eq.) were added to a solution of(2S)-3-aminopropane-1,2-diol (3.00 g, 32.93 mmol, 1.00 eq.) in water(35.00 mL). The mixture was stirred at 25° C. for 16 hours. TLC(DCM:MeOH=5:1) showed that the reaction was complete. The mixture wasextracted by DCM (25 mL×2). The aqueous phase was neutralized with HCland then concentrated under vacuum. The solid residue was suspended inanhydrous ethanol and the inorganic salt was filtered off. The filteratewas concentrated under vacuum to give compound 18A.

Compound 18B

Methylsulfonyl chloride (4.20 g, 36.67 mmol, 2.84 mL, 1.13 eq.) wasadded drop by drop to a solution of(5S)-5-(hydroxymethyl)oxazolidin-2-one (3.80 g, 32.45 mol, 1.00 eq.) andpyridine (37.24 g, 470.85 mmol, 38.00 mL, 14.51 eq.) in dichloromethane(60.00 mL) under N₂ protection at 0° C. The mixture was stirred for 3hours at 0° C. and in nitrogen atmosphere. TLC (DCM:MeOH=10:1) showedthat the reaction was complete. The reaction mixture was concentratedunder vacuum, the residue was purified by column chromatography(DCM/MeOH=200/1 to 100:1) to give compound 18B. ¹H NMR (400 MHz,DMSO-d6) δ ppm 7.65 (br s, 1H), 3.94-3.76 (m, 1H), 4.43-4.37 (m, 1H),4.35-4.28 (m, 1H), 3.58 (t, J=9.2 Hz, 1H), 3.24 (s, 3H).

Compound 18C

N-methylmethylamine (2 M, tetrahydrofuran solution, 30.00 mL) was addedto the mixture of ((5S)-2-oxazolidin-5-yl) methyl sulfonate (450.00 mg,2.31 mmol, 1.00 eq.) in ethanol (5.00 mL), and the obtained reactionsolution was stirred in a sealed tank at 120° C. for 20 hours. TLC(DCM:MeOH=10:1, PMA) test indicated no residual raw materials. Themixture was concentrated. The residue was added with ethyl acetate (30mL), washed with saturated sodium bicarbonate solution (30 mL×1), driedover anhydrous sodium sulfate (10 g) and concentrated to give compound18C. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.42-6.25 (m, 0.4H), 4.07-3.92 (m,0.3H), 3.66-3.57 (m, 0.4H), 3.48-3.34 (m, 0.7H), 3.20-3.07 (m, 0.6H),3.02-2.86 (m, 1H), 2.78 (s, 3H), 2.33-2.25 (m, 1H), 2.20 (s, 3H),2.18-2.12 (m, 1H).

Compound 18

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with (5S)-5-[(dimethylamino)methyl]oxazolidin-2-one to givecompound 18. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 8.47 (s, 1H), 8.40 (s,1H), 7.60 (dd, J=6.8 6.8 Hz, 1H), 7.48-7.36 (m, 1H), 7.31 (s, 1H),7.28-7.19 (m, 1H), 5.16-5.02 (m, 1H), 4.28-4.19 (m, 1H), 4.07 (s, 3H),3.86-3.77 (m, 1H), 3.19-3.06 (m, 1H), 3.02-2.90 (m, 1H), 2.60 (s, 6H).LCMS (ESI) (5-95AB):m/z: 446.1 [M+1].

Example 19 Compound 19A

According to the preparation method of compound 16B,3-(4-hydroxy-7-methoxyquinazolin-6-yl)-2-oxo-1-oxa-3,8-diazaspiro[3.4]octane-2-carboxylicacid tert-butyl ester was replaced with6-bromo-7-methoxyquinazolin-4-ol, and 4-chlorophenol was replaced with4-chloro-1H-indole to give compound 19A. ¹H NMR (400 MHz, deuteratedchloroform) δ=9.19 (s, 1H), 8.33 (s, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.68(d, J=3.5 Hz, 1H), 7.49 (s, 1H), 7.33-7.24 (m, 2H), 7.01 (d, J=3.5 Hz,1H), 4.14 (s, 3H). LCMS (ESI) (5-95AB): m/z: 390.1 [M+1].

Compound 19B

At 25° C. and under nitrogen protection, trans-cyclohexanediamine (11.75mg, 102.92 mmol, 12.64 mL), cuprous iodide (49.00 mg, 257.30 mmol) andpotassium carbonate (213.37 mg, 1.54 mmol) were added to a solution ofcompound 19A (200.00 mg, 514.60 mmol) and compound 2C (131.89 mg, 514.60mmol) in 1,4-dioxane (2.00 mL). The reaction solution was stirred at120° C. for 18 hours. LCMS detected product generation in the reaction.The reaction liquid was filtered and the filter cake was washed withdichloromethane 80 mL (40 mL*2). The filtrate was concentrated to give acrude product. The crude product was purified by TLC (dichloromethane:methanol=20:1) to give compound 19B. ¹H NMR (400 MHz, deuteratedchloroform) δ=9.16 (s, 1H), 8.15 (s, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.74(d, J=3.5 Hz, 1H), 7.53 (s, 1H), 7.29-7.23 (m, 2H), 6.98 (d, J=3.5 Hz,1H), 4.10 (s, 3H), 3.97-3.83 (m, 2H), 3.76 (s, 2H), 3.42-3.25 (m, 2H),2.10-1.99 (m, 2H), 1.76 (br s, 2H), 1.48 (s, 9H). LCMS (ESI) (5-95AB):m/z: 564.4[M+1].

Compound 19C

According to the preparation method of compound 1J,4-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester was replaced with3-(4-(4-chloro-1H-indol-1-yl)-7-methoxyquinazolin-6-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylicacid tert-butyl ester to give compound 19C. The crude product would beused directly for the next step. LCMS (ESI) (5-95AB): m/z: 464.0 [M+1].

Compound 19

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with3-(4-(4-chloro-1H-indol-1-yl)-7-methoxyquinazolin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decane-2-oneto give compound 19. ¹H NMR (400 MHz, METHANOL-d4) δ=9.15 (s, 1H), 8.20(s, 1H), 7.90 (d, J=3.4 Hz, 1H), 7.85-7.79 (m, 1H), 7.64 (s, 1H),7.30-7.23 (m, 2H), 6.97 (d, J=3.4 Hz, 1H), 4.17 (s, 3H), 3.93 (s, 2H),3.20 (br d, J=6.5 Hz, 2H), 3.11 (br s, 2H), 2.74 (br s, 3H), 2.34-2.25(m, 2H), 2.21-2.04 (m, 2H). LCMS (ESI) (5-95AB): m/z: 478.1 [M+1].

Example 20 Compound 20A

1-Benzyl-3-methyl-piperidin-4-one (4.50 g, 22.14 mmol) and Boc₂O (6.28g, 28.78 mmol) were dissolved in ethanol (20.00 mL), and then added withPd—C (10%, 1 g) in nitrogen atmosphere. The reaction system wasvacuumed, displaced with nitrogen gas three times and with hydrogen gasthree times, and the reaction solution was stirred under hydrogenatmosphere (50 psi) at 30° C. for 5 hours. TLC showed that new productsappeared and the raw materials were completely consumed. The reactionsolution was filtered by DCM:MeOH=10:1 (22 mL), concentrated, separatedand purified by column chromatography (PE:EA=3:1) to give compound20A.¹H NMR (400 MHz, deuterated chloroform) δ=4.48-4.14 (m, 2H),3.35-3.17 (m, 1H), 2.85 (br s, 1H), 2.59-2.35 (m, 3H), 1.51-1.47 (m,9H), 1.05 (d, J=6.8 Hz, 3H).

Compound 20B

According to the preparation method of compound 2A,4-oxoperidine-1-formic acid tert-butyl ester was replaced with3-methyl-4-oxoperidine-1-formic acid tert-butyl ester to give compound20B. ¹H NMR (400 MHz, deuterated chloroform) δ=4.20-4.17 (m, 2H), 3.45(s, 2H), 2.77-2.55 (m, 2H), 2.52-2.37 (m, 2H), 2.34-1.79 (m, 3H), 1.45(s, 9H), 1.29-1.27 (m, 3H), 0.95-0.88 (m, 3H).

Compound 20C

According to the preparation method of compound 2B,4-(2-ethoxy-2-oxoethyl)-4-hydroxyperidine-1-formic acid tert-butyl esterwas replaced with4-(2-ethoxy-2-oxoethyl)-4-hydroxy-3-methylpiperidine-1-formic acidtert-butyl ester to give compound 20C. ¹H NMR (400 MHz, deuteratedchloroform) δ=3.98-3.63 (m, 1H), 3.43-3.03 (m, 1H), 2.91-2.52 (m, 2H),2.39-2.23 (m, 1H), 2.11 (s, 2H), 1.89-1.69 (m, 1H), 1.86-1.57 (m, 1H),1.45 (s, 9H), 0.99-0.88 (m, 3H).

Compound 20D

According to the preparation method of compound 2C,2-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)acetic acid wasreplaced with2-(1-(tert-butoxycarbonyl)-4-hydroxy-3-methylpiperidin-4-yl)acetic acidto give compound 20D. ¹H NMR (400 MHz, deuterated chloroform) δ=5.74 (brs, 1H), 3.53-3.44 (m, 1H), 3.33-3.18 (m, 2H), 2.87-2.77 (m, 1H),2.09-1.79 (m, 2H), 1.75-1.63 (m, 2H), 1.46 (s, 9H), 1.13 (t, J=7.2 Hz,1H), 1.01-0.93 (m, 3H).

Compound 20E

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with6-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-formic acid tert-butylester to give compound 20E. ¹H NMR (400 MHz, METHANOL-d4) δ=8.52-8.31(m, 2H), 7.52 (br t, J=6.7 Hz, 1H), 7.43-7.36 (m, 1H), 7.28 (s, 1H),7.24-7.16 (m, 1H), 4.04 (s, 3H), 3.52-3.49 (m, 1H), 3.28-3.21 (m, 3H),1.97-1.90 (m, 2H), 1.77-1.69 (m, 2H), 1.46 (s, 9H), 1.13 (d, J=5.7 Hz,1H), 0.97-0.95 (m, 3H). LCMS (ESI) (5-95AB): m/z: 572.2 [M+1].

Compound 20F

According to the preparation method of compound 1J,4-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester was replaced with3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-6-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylicester to give compound 20F. The crude product would be used directly forthe next step. ¹H NMR (400 MHz, METHANOL-d4) δ=8.78 (s, 1H), 8.66 (s,1H), 7.63-7.48 (m, 2H), 7.44 (s, 1H), 7.31 (dt, J=1.4, 8.1 Hz, 1H), 4.15(s, 3H), 3.28-2.87 (m, 4H), 2.46-2.16 (m, 4H), 1.21 (d, J=2.3 Hz, 1H),1.13-1.01 (m, 3H). LCMS (ESI) (5-95AB): m/z: 472.1 [M+1].

Compound 20

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-6-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-oneto give compound 20. The purity was verified by high performance liquidchromatography and liquid chromatography mass spectrometrysimultaneously. ¹H NMR (400 MHz, METHANOL-d4) δ=8.45 (s, 1H), 8.41 (s,1H), 7.60-7.49 (m, 1H), 7.41 (dt, J=1.5, 7.4 Hz, 1H), 7.32 (s, 1H), 7.22(dt, J=1.3, 8.1 Hz, 1H), 4.11-4.07 (m, 1H), 4.06 (s, 3H), 3.85-3.77 (m,1H), 3.41-3.32 (m, 1H), 3.28-3.02 (m, 2H), 2.83 (br t, J=12.3 Hz, 1H),2.77 (s, 2H), 2.61 (s, 1H), 2.42-2.13 (m, 3H), 1.24-1.15 (m, 3H). LCMS(ESI) (5-95AB): m/z: 486.1 [M+1].

Example 21 Compound 21A

Under nitrogen protection at −70° C., LDA (2 M, 158.09 mL, 2.52 eq.) wasadded dropwise to a solution of 4-oxoperidine-1-formic acid tert-butylester (25.00 g, 125.47 mmol, 1.00 eq.) in THF (200.00 mL). Thirtyminutes later, ethylene iodide (78.27 g, 501.88 mmol, 40.14 mL, 4.00eq.) was added to the above solution at −70° C., and then the mixturewas stirred at room temperature (30° C.) for 16 hours. TLC showed thatthere were still raw materials left. The reaction solution was quenchedwith saturated ammonium chloride solution (100 mL) and partitionedbetween ethyl acetate (100 mL) and water (200 mL). The aqueous solutionwas extracted with ethyl acetate (100 mL×1). The combined organic layerswere washed with brine (100 mL×2), dried over anhydrous sodium sulfate(50 g), and concentrated to a light yellow oily substance. The residuewas purified by silica gel column chromatography (petroleum ether: ethylacetate=20:1) to give compound 21A. LCMS (ESI) (5-95AB): m/z: 128.1[M+1-100].

Compound 21B

According to the preparation method of compound 2A,4-oxoperidine-1-formic acid tert-butyl ester was replaced with3-ethyl-4-oxoperidine-1-formic acid tert-butyl ester to give compound21B. LCMS (ESI) (5-95AB): m/z: 216.1 [M+1-100].

Compound 21C

According to the preparation method of compound 2B,4-(2-ethoxy-2-oxoethyl)-4-hydroxyperidine-1-formic acid tert-butyl esterwas replaced with4-(2-ethoxy-2-oxoethyl)-4-hydroxy-3-ethylpiperidine-1-formic acidtert-butyl ester to give compound 21C. ¹H NMR (400 MHz, deuteratedchloroform) δ=3.90-2.94 (m, 3H), 2.89-2.50 (m, 1H), 2.46-2.11 (m, 1H),2.19 (d, J=15.6 Hz, 1H), 1.95 (s, 2H), 1.68-1.49 (m, 1H), 1.46-1.36 (m,1H), 1.30 (s, 9H), 1.19-0.97 (m, 2H), 0.85-0.76 (m, 2H).

Compound 21D

According to the preparation method of compound 2C,2-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)acetic acid wasreplaced with2-(1-(tert-butoxycarbonyl)-4-hydroxy-3-ethylpiperidin-4-yl)acetic acidto give compound 21D. ¹H NMR (400 MHz, deuterated chloroform) δ=5.79 (brs, 1H), 3.96-3.76 (m, 1H), 3.56-3.18 (m, 4H), 2.03-1.85 (m, 1H),1.75-1.60 (m, 3H), 1.46 (s, 9H), 1.34-1.10 (m, 2H), 1.07-0.95 (m, 3H).

Compound 21E

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 6-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-formicacid tert-butyl ester to give compound 21E. ¹H NMR (400 MHz,METHANOL-d4) δ=8.61-8.25 (m, 2H), 7.55 (br s, 1H), 7.41 (br t, J=7.3 Hz,1H), 7.32 (br s, 1H), 7.27-7.19 (m, 1H), 4.06 (s, 3H), 3.81-3.75 (m,2H), 3.53 (br d, J=9.3 Hz, 2H), 1.97-1.86 (m, 3H), 1.75-1.64 (m, 4H),1.48 (s, 9H), 1.03-1.01 (m, 3H). LCMS (ESI) (5-95AB): m/z: 586.3 [M+1].

Compound 21F

According to the preparation method of compound 1J,4-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester was replaced with3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-6-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylicacid tert-butyl ester to give compound 21F. The crude product would beused directly for the next step. ¹H NMR (400 MHz, METHANOL-d4) δ=8.78(s, 1H), 8.71-8.61 (m, 1H), 7.61-7.48 (m, 2H), 7.43 (s, 1H), 7.36-7.27(m, 1H), 4.15 (s, 3H), 3.85-3.37 (m, 5H), 3.24-2.86 (m, 2H), 2.47-2.08(m, 4H), 1.14-1.04 (m, 3H). LCMS (ESI) (5-95AB): m/z: 486.1 [M+1].

Compound 21

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-6-ethyl-1-oxa-3,8-diazaspiro[4.5]decane-2-oneto give compound 21. The purity was verified by high performance liquidchromatography and liquid chromatography mass spectrometrysimultaneously. ¹H NMR (400 MHz, METHANOL-d4) δ=8.48-8.37 (m, 3H),7.59-7.49 (m, 1H), 7.39 (br t, J=7.4 Hz, 1H), 7.32-7.26 (m, 1H),7.24-7.16 (m, 1H), 4.15-4.08 (m, 1H), 4.07-4.00 (m, 3H), 3.90-3.76 (m,1H), 3.62-3.40 (m, 2H), 3.23 (br t, J=11.8 Hz, 1H), 2.95 (br t, J=12.4Hz, 1H), 2.79-2.89 (m, 3H), 2.49-2.00 (m, 4H), 1.48-1.30 (m, 1H), 1.10(br t, J=7.4 Hz, 3H). LCMS (ESI) (5-95AB): m/z: 500.1 [M+1].

Example 22 Compound 22A

According to the preparation method of compound 1B,2-amino-5-bromo-4-methoxybenzoic acid was replaced with2-amino-5-bromo-4-methylbenzoic acid to give compound 22A. ¹H NMR (400MHz, DMSO-d6) δ=8.21-8.19 (m, 1H), 8.10 (s, 1H), 7.68 (s, 1H), 2.48 (s,3H), 2.18 (s, 1H), 1.75 (s, 1H). LCMS (ESI) (5-95AB): m/z:238.9 [M+1].

Compound 22B

According to the preparation method of compound 1C,6-bromo-7-methoxyquinazolin-4-ol was replaced with6-bromo-7-methoxyquinazolin-4-ol to give compound 22B. ¹H NMR (400 MHz,DMSO-d6) δ=8.30 (s, 1H), 8.22 (s, 1H), 7.70 (s, 1H), 3.28 (s, 1H),3.20-3.16 (m, 1H), 2.93 (s, 1H), 2.34-2.25 (m, 2H). LCMS (ESI) (5-95CD):m/z:258.8[M+1].

Compound 22C

According to the preparation method of compound 1D,6-bromo-4-chloro-7-methoxyquinazoline was replaced with6-bromo-4-chloro-7-methylquinazoline to give 22C. 1H NMR (400 MHz,deuterated chloroform) δ=8.79 (s, 1H), 8.53-8.47 (m, 1H), 8.11 (s, 1H),7.82 (s, 1H), 7.55 (br s, 1H), 7.20-7.16 (m, 2H), 2.61 (s, 3H). LCMS(ESI) (5-95AB): m/z:367.8 [M+1].

Compound 22D

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-formic acidtert-butyl ester, and6-bromo-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine wasreplaced with6-bromo-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine to givecompound 22D. ¹H NMR (400 MHz, deuterated chloroform) δ=8.76 (s, 1H),8.45-8.36 (m, 1H), 7.87 (s, 1H), 7.76 (s, 1H), 7.58 (br s, 1H),7.20-7.16 (m, 2H), 3.94 (br s, 2H), 3.76 (s, 2H), 3.49 (d, J=4.4 Hz,1H), 3.45-3.33 (m, 2H), 2.46 (s, 3H), 2.15 (br d, J=13.8 Hz, 2H),1.91-1.80 (m, 2H), 1.49 (s, 9H), 1.46 (s, 1H). LCMS (ESI) (5-95AB):m/z:542.0 [M+1].

Compound 22E

According to the preparation method of compound 1J,4-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester was replaced with3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylicacid tert-butyl ester to give compound 22E. The crude product would beused directly for the next step. LCMS (ESI) (5-95AB): m/z:442.1 [M+1].

Compound 22

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-1-oxa-3.8-diazaspiro[3.4]decane-2-oneto give compound 22. The purity was verified by high performance liquidchromatography and liquid chromatography mass spectrometrysimultaneously. ¹H NMR (400 MHz, DMSO-d6) δ=9.98 (br s, 1H), 8.53-8.48(m, 1H), 8.46 (br s, 1H), 8.20 (s, 1H), 7.74 (br s, 1H), 7.50 (br s,2H), 7.32-7.26 (m, 1H), 3.88 (s, 2H), 2.52 (br d, J=1.8 Hz, 4H), 2.43(s, 3H), 2.26 (s, 3H), 2.06-1.90 (m, 4H). LCMS (ESI) (5-95CD): m/z:456.1[M+1].

Example 23 Compound 23A

Sodium (117.71 mg, 5.12 mmol,) was added to methanol (20.00 mL) at 25°C. and stirred for 10 minutes. After the solid was dissolved, themixture was added with (((5S)-2-oxazolidin-2-yl)pyridin-5-yl)methylsulfonate (500.00 mg, 2.56 mmol), and stirred at 65° C. for 16hours. TLC (DCM:MeOH=10:1) showed that the reaction was complete and newpoints appeared. The mixture was concentrated, and the residue was addedwith water (20 mL) and extracted with dichloromethane (20 mL×2). Theorganic substance was discarded. The aqueous layer was adjusted to pH=6with 1N HCl and extracted with dichloromethane (20 mL×3). The combinedorganic layers were washed with water (30 mL×1), dried over anhydroussodium sulfate (5 g) and concentrated to give compound 23A. ¹H NMR (400MHz, DMSO-d6) δ ppm 7.48 (s, 1H), 7.60-7.45 (m, 1H), 3.53-3.51 (m, 1H),3.49-3.44 (m, 2H), 3.34 (s, 1H), 3.30 (s, 3H), 3.20 (s, 1H).

Compound 23

According to the preparation method of compound 11,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with (S)-5-(methoxymethyl) oxazolidin-2-one to givecompound 23. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 8.52-8.42 (m, 1H), 8.38(s, 1H), 7.62-7.51 (m, 1H), 7.47-7.37 (m, 1H), 7.31 (s, 1H), 7.25-7.20(m, 1H), 5.00-4.94 (m, 1H), 4.25-4.14 (m, 1H), 4.06 (s, 3H), 3.95-3.87(m, 1H), 3.79-3.64 (m, 2H), 3.50 (s, 3H). LCMS (ESI) (5-95AB):m/z: 433.0[M+1].

Example 24 Compound 24A

According to the preparation method of compound 1D,3-chloro-2-fluoroaniline was replaced with 3-chloro-2,6-difluoroanilineto give compound 24A. LCMS (ESI) (5-95AB):m/z: 401.9 [M+1].

Compound 24B

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-formic acidtert-butyl ester, and6-bromo-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine wasreplaced with6-bromo-N-(3-chloro-2,6-difluorophenyl)-7-methoxyquinazolin-4-amine togive compound 24B. LCMS (ESI) (5-95AB):m/z: 576.3 [M+1].

Compound 24C

Compound 24B (50 mg, 49.91 mmol) was added to ethyl acetatehydrochloride (10 mL, 4 M) and stirred at 20° C. for 1 hour. LCMSdetection showed that the reaction was complete. The reaction solutionwas concentrated, added into 5 mL water, adjusted to 8 of the pH valuewith 0.5 mol/L sodium carbonate solution, and extracted withdichloromethane (5 mL×2). The organic phase was dried over anhydroussodium sulfate (0.5 g), filtered, concentrated, and purified by usingpreparated silica gel chromatography plates to give compound 24C.

Compound 24

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with3-(4-((3-chloro-2,6-difluorophenyl)amino)-7-methoxyquinazolin-6-yl)-1-oxa-3,8-diazaspiro[4.5]detane-2-oneto give compound 24. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 8.46 (br s, 3H), 8.43 (s, 2 H), 7.47-7.61 (m, 1 H), 7.37 (s, 1 H), 7.18 (td, J=9.1,1.9 Hz, 1 H), 4.09 (s, 3 H), 3.95 (s, 2 H), 2.93-3.28 (m, 4 H), 2.71 (brs, 3 H), 2.25-2.40 (m, 2 H), 2.19 (br d, J=10.0 Hz, 2 H). LCMS (ESI)(5-95AB):m/z: 490.3 [M+1].

Example 25 Compound 25

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with7-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-5-oxa-2,7-diazaspiro[3.4]octane-6-one,and polyformaldehyde was replaced with acetaldehyde to give compound 25.¹H NMR (400 MHz, METHANOL-d₄) δ=8.47 (s, 1H), 8.39 (s, 1H), 8.58-8.24(m, 1H), 7.65-7.55 (m, 1H), 7.47-7.39 (m, 1H), 7.34 (s, 1H), 7.30-7.20(m, 1H), 4.33 (s, 2H), 4.19-4.09 (m, 4H), 3.02 (q, J=7.2 Hz, 2H), 1.18(t, J=7.2 Hz, 3H). LCMS (ESI) (5-95AB):m/z: 458.1 [M+1].

Example 26 Compound 26

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with7-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-5-oxa-2,7-diazaspiro[3.4]octane-6-one,and polyformaldehyde was replaced with acetone to give compound 26. ¹HNMR (400 MHz, METHANOL-d₄) δ=8.47 (s, 1H), 8.39 (s, 1H), 7.65-7.54 (m,1H), 7.47-7.38 (m, 1H), 7.33 (s, 1H), 7.28-7.19 (m, 1H), 4.30 (s, 2H),4.07 (s, 3H), 3.95-3.84 (m, 4H), 2.89-2.76 (m, 1H), 1.12 (d, J=6.4 Hz,6H). LCMS (ESI) (5-95AB):m/z: 472.0 [M+1].

Example 27 Compound 27A

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 6-oxo-5-oxa-2.7-diazaspiro[3.4]octane-2-carboxylicacid tert-butyl ester, and6-bromo-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine wasreplaced with 6-bromo-7-methoxyquinazolin-4-ol to give compound 27A.LCMS (ESI) (5-95AB): m/z: 403.1 [M+1].

Compound 27B

According to the preparation method of compound 16B,3-(4-hydroxy-7-methoxyquinazolin-6-yl)-2-oxo-1-oxa-3,8-diazaspiro[3.4]octane-2-carboxylicacid tert-butyl ester was replaced with7-(4-hydroxy-7-methoxyquinazolin-6-yl)-6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylicacid tert-butyl ester to give compound 27B. LCMS (ESI) (5-95AB): m/z:513.2 [M+1].

Compound 27C

According to the preparation method of compound 24C,3-(4-((3-chloro-2,6-difluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]-8-methylformate was replaced with7-(4-(3-chlorophenoxy)-7-methoxyquinazolin-6-yl)-6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylicacid tert-butyl ester to give compound 27C. The crude product would beused directly for the next step.

Compound 27

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with7-(4-(3-chlorophenoxy)-7-methoxyquinazolin-6-yl)-5-oxa-2,7-diazaspiro[3.4]octane-6-oneto give compound 27. The purity was verified by high performance liquidchromatography and liquid chromatography mass spectrometrysimultaneously. ¹H NMR (400 MHz, deuterated chloroform) δ=8.63 (s, 1H),8.40 (s, 1H), 7.51-7.42 (m, 2H), 7.41-7.31 (m, 2H), 7.28-7.18 (m, 1H),4.26 (s, 2H), 4.08 (s, 3H), 3.68-3.59 (m, 4H), 2.44 (s, 3H),LCMS (ESI)(5-95AB): m/z: 427.1 [M+1].

Example 28 Compound 28A

The mixture of 6-bromo-4-chloro-7-methoxy-quinazoline (100.00 mg, 345.54mmol) and anhydrous aluminium trichloride (150.00 mg, 1.12 mmol, 61.48μL, 3.26 eq.) in ethylene glycol dimethyl ether (1.50 mL) was heated upto 80° C., then added with a solution of 1-methylindole (100.00 mg,762.37 mmol) in ethylene glycol dimethyl ether (500.00 μL) and stirredat 80° C. for 2 hours. TLC (PE:EA=1:1) showed that the reaction wascomplete. LCMS showed products were formed. The mixture was cooled downto 20° C., and added with water (10 mL) to form a suspension. Themixture was filtered. The filter cake was washed with water (5 mL×1) andthen dried on a rotary evaporator. The residue was purified by silicagel (PE:EA=10:1 to 1:1 to DCM:MeOH=50:1) to give compound 28A. ¹H NMR(400 MHz, deuterated chloroform) δ=9.15 (s, 1H), 8.51 (s, 1H), 8.04 (d,J=8.0 Hz, 1H), 7.62 (s, 1H), 7.40-7.21 (m, 4H), 4.02 (s, 3H), 3.89 (s,3H). LCMS (ESI) (5-95AB):m/z: 367.9 [M+1].

Compound 28B

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 6-oxo-5-oxa-2,7-diazaspiro[3.4]decane-2-carboxylicacid tert-butyl ester, and6-bromo-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine wasreplaced with 6-bromo-7-methoxy-4-(1-methyl-1H-indol-3-yl) quinazolineto give compound 28B. ¹H NMR (400 MHz, deuterated chloroform) δ=9.16 (s,1H), 8.36 (s, 1H), 8.23 (d, J=7.6 Hz, 1H), 7.72 (s, 1H), 7.40-7.23 (m,4H), 4.38-4.28 (m, 2H), 4.17 (s, 2H), 4.06-3.98 (m, 5H), 3.88 (s, 3H),1.39 (s, 9H). LCMS (ESI) (5-95AB):m/z: 516.1 [M+1].

Compound 28C

According to the preparation method of compound 24C,3-(4-((3-chloro-2,6-difluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]-8-carboxylicacid tert-butyl ester was replaced with7-(7-methoxy-4-(1-methyl-1H-indol-3-yl)quinazolin-6-yl)-6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylicacid tert-butyl ester to give compound 28C. The crude product would beused directly for the next step.

Compound 28

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with 7-(7-methoxy-4-(1-methyl-1H-indol-3-yl)quinazolin-6-yl)-5-oxa-2,7-diazaspiro[3.4]octane-6-one to give compound28. ¹HNMR (400 MHz, METHANOL-d4) δ ppm 9.09 (s, 1 H), 8.60-8.40 (m, 2H), 8.20 (d, J=8.0 Hz, 1 H),7.98 (s, 1 H), 7.55 (d, J=8.4 Hz, 1 H), 7.47(s, 1 H), 7.40-7.30 (m, 1 H), 7.30-7.20 (m, 1 H), 4.30 (s, 2 H), 4.13(s, 3 H), 3.99 (s, 3 H), 3.89 (s, 4 H), 2.61 (s, 3 H). LCMS (ESI)(5-95AB):m/z: 430.1 [M+1].

Example 29 Compound 29

The mixture of 13E and 1-fluoro-2-iodo-ethane in methanol (1.0 mL) wasadded with triethylamine (100.00 mg, 988.24 mmol) and then heated up to70° C. for 4 hours. LCMS detection showed that the reaction wascomplete. The reaction solution was cooled down to 15° C., diluted withmethanol (4 mL) and filtered. The filtrate was purified byhigh-performance liquid chromatography and then by thin-layerchromatography. The obtained product was dissolved in methanol (5 mL)and water (30 mL), added with 2 M hydrochloric acid (1 mL), and thenfreeze dried to give compound 29. ¹H NMR (400 MHz, METHANOL-d4)δ=8.76-8.55 (m, 2H), 7.62-7.46 (m, 2H), 7.42-7.36 (m, 1H), 7.34-7.26 (m,1H), 4.86-4.83 (m, 1H), 4.82-4.64 (m, 5H), 4.47 (s, 2H), 4.13 (s, 3H),3.81-3.68 (m, 2H). LCMS (ESI) (5-95AB):m/z: 476.0 [M+1].

Example 30 Compound 30

13E (90.00 mg, 209.39 mmol) and 1-iodopropane (355.94 mg, 2.09 mmol)were dissolved in methanol (4.00 mL), added with triethylamine (423.76mg, 4.19 mmol) was added to the solution and stirred at 70-80° C. innitrogen atmosphere for 16 hours. The target compound was detected byliquid chromatography mass spectrometry and the raw materials were notcompletely consumed. The reaction mixture was filtered withDCM:MeOH=10:1 (22 mL), concentrated, separated and purified byhigh-performance liquid chromatography, to give compound 30 finally. Thepurity was verified by high performance liquid chromatography and liquidchromatography mass spectrometry simultaneously.

Example 31 Compound 31

Compound 13E (90.00 mg, 209.39 mmol) and(1-ethoxycyclopropoxy)trimethylsilane (145.99 mg, 837.54 mmol) weredissolved in methanol (2.00 mL) and tetrahydrofuran (2.00 mL), addedwith acetic acid (50.29 mg, 837.54 mmol) then added with sodiumcyanoborohydride (52.63 mg, 837.54 mmol) and stirred at 70-80° C. innitrogen atmosphere for 16 hours. The target compound was detected byliquid chromatography mass spectrometry and the raw materials were notcompletely consumed. The reaction mixture was filtered by DCM:MeOH=10:1(22 mL), concentrated, separated and purified by high performance liquidchromatography (HCl condition), to give compound 31 finally. ¹H NMR (400MHz, METHANOL-d4) δ=8.76 (s, 1H), 8.66 (s, 1H), 7.63-7.48 (m, 2H), 7.39(s, 1H), 7.36-7.27 (m, 1H), 4.80-4.71 (m, 4H), 4.46 (s, 2H), 4.16 (s,3H), 3.24-3.18 (m, 1H), 1.09-0.89 (m, 4H). LCMS (ESI) (5-95AB): m/z:470.1 [M+1].

Example 32 Compound 32

According to the preparation method of compound 29,7-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-5-oxa-2,7-diazaspiro[3.4]octane-6-one was replaced with3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decane-2-oneto give compound 32. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.85-8.71 (m, 2H), 7.71-7.53 (m, 2 H), 7.43 (s, 1 H), 7.29-7.18 (m, 1 H), 5.00 (s, 2H), 4.16 (s, 3 H), 4.03 (s, 2 H), 3.74-3.56 (m, 4 H), 3.53-3.41 (m, 2H). 2.65-2.30 (m, 4 H). LCMS (ESI) (5-95AB):m/z: 504.2 [M+1].

Example 33 Compound 33A

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 6-oxo-5-oxa-2,7-diazaspiro[3.4]decane-2-carboxylicacid tert-butyl ester, and6-bromo-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine wasreplaced with 6-bromo-N-(3-chloro-2-fluorophenyl)quinazolin-4-amine togive compound 33A. ¹H NMR (400 MHz, deuterated chloroform) δ=8.78 (s,1H), 8.42-8.33 (m, 1H), 8.26 (s, 1H), 8.01-7.96 (m, 1H), 7.93-7.87 (m,1H), 7.23-7.16 (m, 2H), 4.48-4.42 (m, 2H), 4.38 (s, 2H), 4.22-4.15 (m,2H), 1.50 (s, 9H). LCMS (ESI) (5-95AB): m/z: 500.1 [M+1].

Compound 33B

According to the preparation method of compound 24C,3-(4-((3-chloro-2,6-difluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylicacid tert-butyl ester was replaced with7-(4-(3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)-6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylicacid tent-butyl ester to give compound 33B. The crude product would beused directly for the next step. LCMS (ESI) (5-95AB): m/z: 400.0 [M+1].

Compound 33

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with7-(4-((3-chloro-2-fluorophenyl)amino)quinazolin-6-yl)-5-oxa-2,7-diazaspiro[3.4]octane-6-one,and polyformaldehyde was replaced with acetone to give compound 33. Thepurity was verified by high performance liquid chromatography and liquidchromatography mass spectrometry simultaneously. ¹H NMR (400 MHz,METHANOL-d4) δ=8.95-8.77 (m, 2H), 8.54 (br s, 1H), 8.05-7.95 (m, 1H),7.63-7.53 (m, 2H), 7.38-7.28 (m, 1H), 4.77-4.55 (m, 6H), 3.70-3.60 (m,1H), 1.43-1.25 (m, 6H). LCMS (ESI) (5-95AB): m/z: 442.0 [M+1].

Example 34 Compound 34

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-1-oxa-3,8-diazaspiro[4.5]decane-2-one,and polyformaldehyde was replaced with propanal to give compound 34. ¹HNMR (400 MHz, METHANOL-d4) δ=8.45 (s, 1H), 8.41 (s, 1H), 8.39 (br s,1H), 7.63-7.54 (m, 1H), 7.44-7.36 (m, 1H), 7.30 (s, 1H), 7.25-7.15 (m,1H), 4.05 (s, 3H), 3.94 (s, 2H), 3.54-3.43 (m, 2H), 3.30-3.23 (m, 2H),3.11-3.01 (m, 2H), 2.43-2.18 (m, 4H), 1.88-1.72 (m, 2H), 1.03 (t, J=7.2Hz, 3H). LCMS (ESI) (5-95AB): m/z: 500.2 [M+1].

Example 35 Compound 35A

According to the preparation method of compound 1I,3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl esterwas replaced with 6-oxo-5-oxa-2,7-diazaspiro[3.4]decane-2-carboxylicacid tert-butyl ester, and6-bromo-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine wasreplaced with6-bromo-N-(3,4-dichloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine togive compound 35A. LCMS (ESI) (5-95AB): m/z: 564.1 [M+1].

Compound 35B

According to the preparation method of compound 1J,4-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester was replaced with7-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-6-oxo-5-oxa-2,7-diazaspiro[4.5]octane-2-carboxylicacid tert-butyl ester to give compound 35B. LCMS (ESI) (5-95AB): m/z:464.1 [M+1].

Compound 35

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with7-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-5-oxa-2,7-diazaspiro[3.4]octane-6-oneto give compound 35. ¹H NMR (400 MHz, METHANOL-d4) δ=8.46 (s, 1H), 8.35(s, 1H), 8.31 (br s, 1H), 7.61 (dd, J=8.0 8.0 Hz, 1H), 7.43 (dd, J=2.0,8.8 Hz, 1H), 7.31 (s, 1H), 4.32 (s, 2H), 4.18-4.13 (m, 2H), 4.05 (s,3H), 2.99-2.88 (m, 2H), 1.59-1.51 (m, 2H), 1.04-0.96 (m, 5H). LCMS (ESI)(5-95AB): m/z: 506.1 [M+1].

Example 36 Compound 36A

According to the preparation method of compound 1C,6-bromo-7-methoxyquinazolin-4-ol was replaced with7-(4-hydroxy-7-methoxyquinazolin-6-yl)-6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylicacid tert-butyl ester to give compound 36A. The crude product would beused directly for the next step.

Compound 36B

According to the preparation method of compound 1D,6-bromo-4-chloro-7-methoxyquinazoline was replaced with7-(4-chloro-7-methoxyquinazolin-6-yl)-5-oxa-2,7-diazaspiro[3.4]octane-6-one,and 3-chloro-2-fluoroaniline was replaced with2-fluoro-3-((trimethylsilyl)acetylene)aniline to give compound 36B. LCMS(ESI) (5-95AB): m/z: 492.1 [M+1].

Compound 36

A solution of compound 36B (40.00mg, 81.37 umol, 1.00 eq.) in methanol(2.00 mL) was added with aldehyde (20.00 mg, 344.20 umol, 25.00 uL, 4.23eq.), stirred at 40° C. for 0.5 hours, added with NaBH₃CN (20.00 mg,318.16 umol, 3.91 eq.), and stirred at 40° C. for another 1 hour. Thedetection results indicated that the reductive amination reaction wascomplete. After potassium carbonate (45.00 mg, 325.48 umol) was added tothe reaction solution, the solution was stirred at room temperature for0.5 hours. The product was detected by LCMS. The pH value of thereaction solution was adjusted to pH=6 with 2N hydrochloric acid, andthe solution was concentrated. The residue was diluted with methanol (2mL), and then separated and purified by high performance liquidchromatography to give compound 36. ¹H NMR (400 MHz, METHANOL-d4) δ=8.79(s, 1H), 8.72 (s, 1H), 7.68-7.53 (m, 1H), 7.68-7.53 (m, 1H), 7.41 (s,1H), 7.36-7.27 (m, 1H), 4.83-4.73 (m, 2H), 4.70-4.58 (m, 2H), 4.56-4.41(m, 2H), 4.20 (s, 3H), 3.93 (s, 1H), 3.42-3.34 (m, 2H), 1.80-1.61 (m,2H), 1.11-1.02 (m, 3H). LCMS (ESI) (5-95AB): m/z: 462.1 [M+1].

Examples 37,38 Compound 37A

A tetrahydrofuran solution of compound (3R, 4S)-3-(benzyloxycarbonylamino)-4-hydroxy-pyrrolidine-1-formic acid tert-butyl ester (200 mg,594.56 mmol, 1.00 eq.) was added with potassium tert-butanol (80.06 mg,713.47 mmol, 1.20 eq.), and stirred at 20° C. for 2 hours. TLC detectionshowed that the reaction was complete. The reaction solution wasconcentrated, and the residue was separated by column chromatography togive compound 37A.

Compound 37B

Compound 1D (200.0 mg, 522.72 mmol) and compound 37B (119.31 mg, 522.72mmol) were dissolved in 1,4-dioxane (3 mL), then added with cesiumcarbonate (510.94 mg, 1.57 mmol), cuprous iodide (298.66 mg, 1.57 mmol)and N, N′-dimethyl-1,2-ethylenediamine (138.2mg, 1.57 mmol),respectively and stirred under nitrogen protection at 120° C. for 12hours. TLC showed that the raw materials were not completely consumed.The reaction solution was concentrated, then separated and purified bythin-layer chromatography to give compound 37B. ¹H NMR (400 MHz,deuterated chloroform) δ=8.75 (s, 1H), 8.33 (br s, 1H), 8.04 (br s, 1H),7.82 (br d, J=9.3 Hz, 1H), 7.36 (s, 1H), 7.23-7.11 (m, 2H), 5.25 (t,J=6.1 Hz, 1H), 4.85 (br s, 1H), 4.16 (br d, J=12.7 Hz, 1H), 4.02 (s,3H), 3.58-3.29 (m, 2H), 3.18-2.96 (m, 1H), 1.47 (s, 9H).

Compound 37C

According to the preparation method of compound 1J,4-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-oxo-2-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylicacid tert-butyl ester was replaced with (3aR,6aS)-3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxotetrahydro-2H-pyrrol[3,4-d]oxazol-5(3H)-carboxylicacid tert-butyl ester to give compound 37C, which did not requirepurification. The crude product would be used directly for the nextstep.

Compound 37D

According to the preparation method of compound 1,(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxa-4,9-diazaspiro[5.5]undecane-3-onewas replaced with (3AR,6AS)-3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)hexahydro-2H-pyrrol[3,4-d]oxazol-2-oneto give compound 37D. SFC of the compound showed two peaks, whichindicated that it was a mixture. ¹H NMR (400 MHz, METHANOL-d4) δ=8.47(br s, 1H), 8.33 (s, 1H), 7.56 (t, J=7.4 Hz, 1H), 7.45-7.38 (m, 1H),7.33 (s, 1H), 7.27-7.19 (m, 1H), 5.31 (dd, J=4.5, 8.0 Hz, 1H), 4.97 (dd,J=5.0, 8.0 Hz, 1H), 4.07 (s, 3H), 3.43 (d, J=11.8 Hz, 1H), 3.12 (d,J=11.3 Hz, 1H), 2.51 (dd, J=4.6, 11.9 Hz, 1H), 2.47 (s, 3H), 2.23 (dd,J=5.0, 11.3 Hz, 1H). LCMS (ESI) (5-95AB): m/z: 444.3 [M+1].

Compounds 37 and 38

Compound 37D (21 mg) was weighed and separated by SFC (conditions:Daicel chiral column (250 mm*30 mm, 5 □m), mobile phase (methanolsolution containing 0.1% ammonia water)) to give compound 37 (ee value:100%, retention time (min): 1.142) and compound 38 (ee value: 95.98%,retention time (min): 1.209).

Compound 37: ¹H NMR (400 MHz, METHANOL-d4) δ=8.45 (s, 1H), 8.30 (s, 1H),7.59-7.49 (m, 1H), 7.46-7.39 (m, 1H), 7.33 (s, 1H), 7.24 (dt, J=1.5, 8.1Hz, 1H), 5.28 (dd, J=4.5, 7.9 Hz, 1H), 4.96 (br d, J=4.9 Hz, 1H), 4.07(s, 3H), 3.37 (br d, J=11.7 Hz, 1H), 3.04 (br d, J=10.3 Hz, 1H),2.44-2.39 (m, 4H), 2.18-2.09 (m, 1H). LCMS (ESI) (5-95AB): m/z: 444.3[M+1].

Compound 38: ¹H NMR (400 MHz, METHANOL-d4) δ=8.45 (s, 1H), 8.30 (s, 1H),7.55 (br t, J=7.0 Hz, 1H), 7.43 (t, J=6.7 Hz, 1H), 7.33 (s, 1H), 7.24(dt, J=1.1, 8.1 Hz, 1H), 5.28 (dd, J=4.5, 7.9 Hz, 1H), 4.99-4.94 (m,1H), 4.07 (s, 3H), 3.36 (d, J=12.0 Hz, 1H), 3.03 (d, J=11.0 Hz, 1H),2.44-2.38 (m, 4H), 2.12 (dd, J=5.0, 11.1 Hz, 1H). LCMS (ESI) (5-95AB):m/z: 444.3 [M+1].

Examples 39, 40 Compound 39A

According to the preparation method of compound 13A, nitromethane wasreplaced with 1-nitroethane to give compound 39A. 1H NMR (400 MHz,deuterated chloroform) δ=4.82 (q, J=7.0 Hz, 1H), 4.03-3.95 (m, 2H),3.95-3.86 (m, 2H), 1.67 (d, J=7.0 Hz, 3H), 1.47 (s, 9H).

Compound 39B

According to the preparation method of compound 13B,3-hydroxy-3-(nitromethyl)azacyclobutane-1-formic acid tert-butyl esterwas replaced with 3-hydroxy-3-(1-nitroethyl)azacyclobutane-1-carboxylicacid tert-butyl ester to give compound 39B. 1HNMR (400 MHz, deuteratedchloroform) δ=3.97-3.83 (m, 4H), 3.35-3.28 (m, 1H), 1.46 (s, 9H), 1.10(d, J=6.8 Hz, 3H).

Compound 39C

According to the preparation method of compound 13C, compound 13B wasreplaced with compound 39B to give compound 39C.

Compound 39D

According to the preparation method of compound 1I, compound 1H wasreplaced with compound 39C to give compound 39D. LCMS (ESI) (5-95AB):m/z: 444.1 [M+1-Boc].

Compound 39E

According to the preparation method of compound 1J, compound 1I wasreplaced with compound 39D to give compound 39E.

Compound 39F

According to the preparation method of compound 1, compound 1J wasreplaced with 39E to give compound 39F. SFC showed two peaks, whichindicated that it was a mixture.

Compounds 39 and 40

Compound 39F (75 mg) was weighed and separated by SFC (condition: Daicelchiral column (250 mm*30 mm, 10 □m), mobile phase (ethanol solutioncontaining 0.1% ammonia water, flow rate: 70 ml/min)) to give compound39 (ee value: 100%, retention time (min): 0.826).

¹H NMR (400 MHz, METHANOL-d4) δ=8.42-8.31 (m, 1H), 8.23 (s, 1H), 7.45(br t, J =7.0 Hz, 1H), 7.36-7.26 (m, 1H), 7.22 (s, 1H), 7.16-7.06 (m,1H), 4.48 (br s, 1H), 4.40 (q, J=6.4 Hz, 1H), 3.94 (s, 3H), 3.70 (d,J=9.3 Hz, 1H), 3.57-3.46 (m, 3H), 3.41-3.31 (m, 1H), 2.36 (s, 3H),1.28-1.15 (m, 4H).

Compound 40 (ee value: 100%, retention time (min): 1.098). ¹H NMR (400MHz, METHANOL-d4) δ=8.42-8.31 (m, 1H), 8.23 (s, 1H), 7.45 (br t, J=7.0Hz, 1H), 7.36-7.26 (m, 1H), 7.22 (s, 1H), 7.16-7.06 (m, 1H), 4.48 (br s,1H), 4.40 (q, J=6.4 Hz, 1H), 3.94 (s, 3H), 3.70 (d, J=9.3 Hz, 1H),3.57-3.46 (m, 3H), 3.41-3.31 (m, 1H), 2.36 (s, 3H), 1.28-1.15 (m, 4H).

Examples 41, 42 Compound 41A

DIEA (69.67 g, 539.09 mmol, 1.70 eq.) and isobutyl chloroformate (64.97g, 475.67 mmol, 1.5 eq.) were added to a tetrahydrofuran solution (400mL) of compound 2-(tert-butoxycarbonyl amino) propionic acid (60 g,317.11 mmol, 1.00 eq.) at 0° C. and stirred for 4 hours, then added withdiazomethyl(trimethyl)silane (2 mol, 317.11 mL, 2 eq.), stirred at 0° C.for 2 hours, heated up to 250° C. and stirred for further 6 hours. Thereaction solution was concentrated, and the residue was separated bycolumn chromatography to give compound 41A.

Compound 41B

Rhodium acetate (525.32 mg, 1.88 mmol, 0.02 eq.) and triethylamine(189.82 mg, 1.88 mmol, 0.02 eq.) were added to a dichloromethanesolution (200 mL) of compound 41A (20 g, 93.79 mmol, 1.00 eq.), andstirred at 0° C. for 1 hour. The reaction solution was concentrated togive a green oily substance, and the residue was separated by columnchromatography to compound 41B.

Compound 41C

Nitromethane (16.48 g, 269.95 mmol, 5.00 eq.) and triethylamine (273.16mg, 2.70 mmol, 0.05 eq.) were added to an ethanol solution of compound41B (10 g, 53.99 mmol, 1.00 eq.), and stirred at 250° C. for 12 hours.The reaction solution was concentrated to give a green oily substance,and the crude product was separated by column chromatography to givecompound 41C.

Compound 41D

According to the preparation method of compound 13B,3-hydroxy-3-(nitromethyl)azacyclobutane-1-formic acid tert-butyl esterwas replaced with 41C to give compound 41D. ¹HNMR (400 MHz, DMSO-d6)δ=3.90-3.69 (m, 1H), 3.66-3.37 (m, 2H), 3.35-3.13 (m, 2H), 1.20-1.10 (m,9H), 1.01-0.92 (m, 3H).

Compound 41E

According to the preparation method of compound 13C, compound 13B wasreplaced with compound 41D to give compound 41E. ¹H NMR (400 MHz,deuterated chloroform) δ=4.05-3.96 (m, 1H), 3.47-3.30 (m, 4H), 3.47-3.30(m, 1H), 1.38 (s, 9H), 1.37 (br s, 2H).

Compound 41F

According to the preparation method of compound 1I, 1H was replaced with41E to give compound 41F. 1H NMR (400 MHz, deuterated chloroform) δ=8.60(s, 1H), 8.12-7.99 (m, 2H), 7.80 (br s, 1H), 7.24-7.16 (m, 2H),7.14-7.01 (m, 1H), 4.38-4.29 (m, 1H), 4.25 (d, J=10.3 Hz, 1H), 4.02 (s,3H), 1.49 (d, J=6.6 Hz, 3H), 1.41 (s, 9H).

Compound 41G

According to the preparation method of compound 1J, compound 1I wasreplaced with 41F to give compound 41G.

Compound 41H

According to the preparation method of compound 1, compound 1J wasreplaced with compound 41G. SFC showed two peaks, which indicated thatit was a mixture.

Compounds 41 and 42

Compound 41H was weighed and separated by SFC (condition: Daicel chiralcolumn (250 mm*30 mm, 10 □m), mobile phase (ethanol solution of 0.1%ammonia water)) to give compound 41 (ee value: 100%, retention time(min): 2.368). ¹HNMR (400 MHz, METHANOL-d4) δ=8.36 (s, 1H), 8.23 (s,1H), 7.44 (br t, J=7.1 Hz, 1H), 7.31 (br t, J=6.8 Hz, 1H), 7.21 (s, 1H),7.16-7.09 (m, 1H), 4.76 (s, 16H), 4.39 (q, J=6.5 Hz, 1H), 3.93 (s, 3H),3.70 (d, J=9.3 Hz, 1H), 3.57-3.48 (m, 2H), 3.36 (d, J=9.3 Hz, 1H), 2.36(s, 3H), 1.42-1.24 (m, 1H), 1.24-1.14 (m, 5H), 1.08 (br t, J=7.1 Hz,1H), 0.79 (br d, J=7.1 Hz, 1H).

Compound 42 (ee value: 95.528%, retention time (min): 2.529). ¹H NMR(400 MHz, METHANOL-d4) 8.36 (s, 1H), 8.23 (s, 1H), 7.44 (br t, J=7.1 Hz,1H), 7.31 (br t, J=6.8 Hz, 1H), 7.21 (s, 1H), 7.16-7.09 (m, 1H), 4.76(s, 16H), 4.39 (q, J=6.5 Hz, 1H), 3.93 (s, 3H), 3.70 (d, J=9.3 Hz, 1H),3.57-3.48 (m, 2H), 3.36 (d, J=9.3 Hz, 1H), 2.36 (s, 3H), 1.42-1.24 (m,1H), 1.24-1.14 (m, 5H), 1.08 (br t, J=7.1 Hz, 1H), 0.79 (br d, J=7.1 Hz,1H).

Example 43 Compound 43A

According to the preparation method of compound 1I, compound 1D wasreplaced with compound 6A to give compound 43A. 1H NMR (400 MHz,deuterated chloroform) δ 8.74-8.62 (m, 1H), 8.20-8.13 (m, 1H), 8.11 (s,1H), 7.75 (br s, 1H), 7.32-7.27 (m, 2H), 4.48-4.41 (m, 2H), 4.26 (s,2H), 4.17 (d, J=10.0 Hz, 2H), 3.97 (s, 3H), 1.49 (s, 9H).

Compound 43B

According to the preparation method of compound 1J, compound 1I wasreplaced with 43A to give compound 43B.

Compound 43

According to the preparation method of compound 1, compound 1J wasreplaced with compound 43B to give compound 43. ¹HNMR (400 MHz, DMSO-d₆)δ 9.97 (br s, 1H), 8.48 (br d, J=14.8 Hz, 1H), 8.13 (s, 1H), 7.66-7.49(m, 2H), 7.37 (s, 1H), 4.21 (s, 2H), 4.00 (s, 3H), 3.87-3.60 (m, 4H),2.52 (s, 3H).

Example 44 Compound 44A

According to the preparation method of compound 1I, compound 1D wasreplaced with compound 9A to give compound 44A. 1H NMR (400 MHz,deuterated chloroform) δ=8.76-8.68 (m, 1H), 8.23 (t, J=8.5 Hz, 1H), 8.09(s, 1H), 7.38-7.36 (m, 1H), 7.38-7.35 (m, 1H), 7.35-7.33 (m, 1H),7.32-7.30 (m, 1H), 4.44 (d, J=10.3 Hz, 2H), 4.27 (s, 2H), 4.18 (d,J=10.2 Hz, 2H), 4.01 (s, 3H), 1.49 (s, 9H).

Compound 44B

According to the preparation method of compound 1J, compound 11 wasreplaced with 44A to give compound 44B. LCMS (ESI) (5-95AB): m/z: 473.9[M+1].

Compound 44

According to the preparation method of compound 1, compound 1J wasreplaced with compound 44B to give compound 44. ¹H NMR (400 MHz,METHANOL-d₄) δ=8.46 (s, 1H), 8.43-8.28 (m, 2H), 7.62 (t, J=8.4 Hz, 1H),7.49 (d, J=9.8 Hz, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.32 (s, 1H), 4.32 (s,2H), 4.20-4.11 (m, 4H), 4.09-3.96 (m, 3H), 2.77 (s, 3H). LCMS (ESI)(5-95AB): m/z: 487.9 [M+1].

Example 45 Compound 45A

Pyridine hydrochloride (3.02 g, 26.14 mmol, 5.00 eq.) was added tocompound 1D (2 g, 5.23 mmol, 1.00 eq.), heated up to 170° C. and stirredfor 2 hours. The reaction solution was concentrated, and saturatedsodium bicarbonate solution was added to adjust the solution to PH=9.The residue was extracted with mixed solvent (DCM:MeOH=10:1), and theorganic layer was separated, dried over anhydrous sodium sulfate, andconcentrated. The crude product was separated by column chromatographyto give compound 45A. 1H NMR (400 MHz, DMSO-d6) δ=9.86 (s, 1H), 8.75 (s,1H), 8.41 (s, 1H), 7.50 (q, J=6.9 Hz, 2H), 7.33-7.25 (m, 1H), 7.20 (s,1H).

Compound 45B

Potassium hydroxide (4.26 g, 75.97 mmol, 20.0 eq.) and diethyl(bromodifluoromethyl)phosphonate (2.03 g, 7.60 mmol, 2.0 eq.) were addedto the mixture of acetonitrile (5 mL) and water (5 mL) of compound 45A(1.4 g, 3.80 mmol, 1.00 eq.), and stirred at 20° C. for 12 hours. Thereaction solution was concentrated to give compound 45B. ¹H NMR (400MHz, METHANOL-d4) δ=8.82 (s, 1H), 8.53 (s, 1H), 7.61-7.55 (m, 2H),7.50-7.36 (m, 2H), 7.30-7.20 (m, 2H).

Compound 45C

According to the preparation method of compound 1I, compound 1D wasreplaced with compound 45B to give compound 45C. ¹H NMR (400 MHz,METHANOL-d4) δ=8.63-8.48 (m, 2H), 7.68-7.55 (m, 2H), 7.49-7.43 (m, 1H),7.38 (s, 1H), 7.26 (t, J=8.1 Hz, 1H), 7.20 (s, 1H), 7.02 (s, 1H),4.35-4.19 (m, 4H), 1.50 (s, 9H), 1.47 (s, 2H).

Compound 45D

According to the preparation method of compound 1J, compound 1I wasreplaced with compound 45C to give compound 45D.

Compound 45

According to the preparation method of compound 1, compound 1J wasreplaced with compound 45D to give compound 45. 1H NMR (400 MHz,METHANOL-d4) δ=8.53 (s, 2H), 7.67-7.55 (m, 2H), 7.45 (br t, J=7.5 Hz,1H), 7.38 (s, 1H), 7.31-7.22 (m, 1H), 7.20 (s, 1H), 7.02 (s, 1H), 4.32(s, 2H), 3.73-3.61 (m, 4H), 2.48 (s, 3H).

Example 46 Compound 46A

According to the preparation method of compound 1D,3-chloro-2-fluoroaniline was replaced with 4-chloro-2-fluoroaniline togive compound 46A. ¹HNMR (400 MHz, DMSO-d6) δ=9.15 (s, 1H), 8.71 (s,1H), 7.58 (dt, J=6.1, 8.8 Hz, 1H), 7.49-7.41 (m, 2H), 7.25-7.16 (m, 1H),4.05 (s, 3H).

Compound 46B

According to the preparation method of compound 1I, compound 1D wasreplaced with compound 46A to give compound 46B. ¹H NMR (400 MHz,CHLOROFORM-d) δ=8.70 (s, 1H), 8.30-8.21 (m, 1H), 8.09 (s, 1H), 7.30 (s,1H), 7.23-7.21 (m, 1H), 7.21-7.18 (m, 1H), 4.45 (d, J=10.5 Hz, 2H), 4.27(s, 2H), 4.18 (d, J=10.3 Hz, 2H), 4.00 (s, 3H), 1.50 (s, 9H). LCMS (ESI)(5-95AB): m/z: 530.0 [M+1].

Compound 46C

According to the preparation method of compound 1J, compound 1I wasreplaced with compound 46B to give compound 46C. LCMS (ESI) (5-95AB):m/z: 430.0 [M+1].

Compound 46

According to the preparation method of compound 1, compound 1J wasreplaced with compound 46C to give compound 46. ¹HNMR (400 MHz,METHANOL-d4) δ=8.46 (s, 1H), 8.37 (s, 1H), 7.67 (t, J=8.4 Hz, 1H),7.39-7.25 (m, 3H), 4.30 (s, 2H), 4.09-4.02 (m, 4H), 4.07 (s, 3H), 2.71(s, 3H). LCMS (ESI) (5-95AB): m/z: 444.0 [M+1].

Example 47 Compound 47A

According to the preparation method of compound 1D,3-chloro-2-fluoroaniline was replaced with 2-fluoro-4-methylaniline togive compound 47A. ¹H NMR (400 MHz, DMSO-d6) δ=9.08 (s, 1H), 8.71 (s,1H), 7.45-7.37 (m, 2H), 7.21 (d, J=11.4 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H),4.06 (s, 3H), 2.38 (s, 3H).

Compound 47B

According to the preparation method of compound 1I, compound 1D wasreplaced with compound 47A to give compound 47B. ¹H NMR (400 MHz,deuterated chloroform) δ=8.73 (s, 1H), 8.19 (t, J=8.3 Hz, 1H), 7.99 (s,1H), 7.37 (s, 1H), 7.06-7.01 (t, 2H), 4.45 (d, J=10.3 Hz, 2H), 4.27 (s,2H), 4.17 (d, J=10.0 Hz, 2H), 4.04 (s, 3H), 2.39 (s, 3H), 1.50 (s, 9H).LCMS (ESI) (5-95AB): m/z: 510.1 [M+1].

Compound 47C

According to the preparation method of compound 1J, compound 1I wasreplaced with compound 47B to give compound 47C. LCMS (ESI) (5-95AB):m/z: 410.3 [M+1].

Compound 47

According to the preparation method of compound 1, compound 1J wasreplaced with 47C to give compound 47. 1H NMR (400 MHz, METHANOL-d4)δ=8.41 (s, 1H), 8.37 (s, 1H), 7.47 (t, J=8.2 Hz, 1H), 7.32 (s, 1H),7.12-7.04 (m, 2H), 4.28 (s, 2H), 4.07 (s, 3H), 3.92-3.79 (m, 4H),2.62-2.55 (m, 3H), 2.42 (s, 3H). LCMS (ESI) (5-95AB): m/z: 424.1 [M+1].

Example 48 Compound 48A

According to the preparation method of compound 1D,3-chloro-2-fluoroaniline was replaced with 2-fluoro-3-methylaniline togive compound 48A. ¹H NMR (400 MHz, DMSO-d6) δ=11.77 (br s, 1H), 9.29(s, 1H), 8.87 (s, 1H), 7.53 (s, 1H), 7.41-7.28 (m, 2H), 7.28-7.15 (m,1H), 4.07 (s, 3H), 2.31 (s, 3H).

Compound 48B

According to the preparation method of compound 1I, compound 1D wasreplaced with compound 48A to give compound 48B. ¹H NMR (400 MHz,deuterated chloroform) δ=8.63 (s, 1H), 8.10 (t, J=7.5 Hz, 1H), 7.94 (s,1H), 7.53-7.43 (m, 1H), 7.21 (s, 1H), 7.02 (t, J=7.9 Hz, 1H), 6.94-6.86(m, 1H), 4.36 (d, J=10.9 Hz, 2H), 4.17 (s, 2H), 4.11-4.06 (m, 2H), 3.90(s, 3H), 2.26 (d, J=2.0 Hz, 3H), 1.41 (s, 9H). LCMS (ESI) (5-95AB): m/z:510.1 [M+1].

Compound 48C

According to the preparation method of compound 1J, compound 1I wasreplaced with compound 48B to give compound 48C. LCMS (ESI) (5-95AB):m/z: 410.1 [M+1].

Compound 48

According to the preparation method of compound 1, compound 1J wasreplaced with compound 48C to give compound 48. 1HNMR (400 MHz,METHANOL-d4) δ=8.42 (s, 1H), 8.38 (s, 1H), 8.33 (br s, 1H), 7.47-7.40(m, 1H), 7.30 (s, 1H), 7.23-7.17 (m, 1H), 7.16-7.10 (m, 1H), 4.39-4.28(m, 2H), 4.25-4.13 (m, 4H), 4.06 (s, 3H), 2.79 (s, 3H), 2.34 (d, J=1.7Hz, 3H). LCMS (ESI) (5-95AB): m/z: 424.2 [M+1].

Example 49 Compound 49A

According to the preparation method of compound 1D,3-chloro-2-fluoroaniline was replaced with 2,4-dichloro-3-methylanilineto give compound 49A. ¹H NMR (400 MHz, DMSO-d₆) δ=9.03 (s, 1H), 8.61 (s,1H), 7.62-7.54 (m, 1H), 7.48-7.38 (m, 2H), 4.04 (s, 3H).

Compound 49B

According to the preparation method of compound 1I, compound 1D wasreplaced with 49A to give compound 49B. ¹HNMR (400 MHz, deuteratedchloroform) δ=8.63 (s, 1H), 8.20 (s, 1H), 7.95-7.66 (m, 2H), 7.21 (s,1H), 4.44 (d, J=10.3 Hz, 2H), 4.26 (s, 2H), 4.18 (d, J=10.4 Hz, 2H),3.95 (s, 3H), 1.50 (s, 9H). LCMS (ESI) (5-95AB): m/z: 548.0 [M+1].

Compound 49C

According to the preparation method of compound 1J, compound 11 wasreplaced with 49B to give compound 49C. LCMS (ESI) (5-95AB): m/z: 448.1[M+1].

Compound 49

According to the preparation method of compound 1, compound 1J wasreplaced with 49C to give compound 49. 1H NMR (400 MHz, deuteratedchloroform) δ=8.64 (s, 1H), 8.17 (s, 1H), 7.87 (dt, J=5.6, 8.8 Hz, 1H),7.80 (br s, 1H), 7.22 (s, 1H), 7.05-6.97 (m, 1H), 4.30 (s, 2H), 3.96 (s,3H), 3.69 (d, J=9.2 Hz, 2H), 3.51 (d, J=9.2 Hz, 2H), 2.48 (s, 3H). LCMS(ESI) (5-95AB): m/z: 462.2 [M+1]

Biochemical Experiments: The Purpose of the Experiment is:

Detection of inhibitory effects of compounds on enzymatic activities ofEGFR WT, EGFR [L858R] and EGFR [d746-750]

Examperimental Materials:

EGFR WT (Invitrogen, Cat.No PR7295B), EGFR [L858R] (Invitrogen, Cat.NoPR7447A), EGFR [d746-750](Invitrogen, Cat.No PV6179), ATP (Sigma, Cat.No. A7699-1G), DMSO (Sigma, Cat. No. D2650), DTT (Sigma, Cat. No.43815), 384-well plates compound dilution plates (Greiner, Cat. No.781280), 384-well plates _test plates (Perkin Elmer, Cat. No.6007299),HTRF KinEASE TK Kit (Cisbio, Cat. No. 62TKOPEB), MgCl₂ (Sigma, Cat. No.M1028), Orthovanadate (Sigma, Cat. No. S6508), BSA (Sigma, Cat. No.A7030), HEPES (Life technology, Cat. No. 11344-041)

Experimental Methods: Final Test Concentrations of Compounds:

The final test concentrations of the test compounds ranged from 10 μM to0.17 nM, with serial 3-fold dilutions and 11 gradient concentrations.

Kinase Assay:

Buffer formulation: a buffer consisted of 50 mM HEPES (pH 7.5), 0.01%BSA, 5 mM MgCl₂, 0.1 mM Orthovanadate. After the buffer was formulated,an enzyme and a substrate were mixed with pre-diluted compounds ofvarying concentrations, and placed at room temperature for 15 minutes.The reaction was initiated by adding ATP and incubated at roomtemperature for 60 minutes (wherein negative and positive controls wereset up). The 10 μL reaction system consisted of a 2.5 μL compound, a 5μL mixture of enzyme and substrate, and 2.5 μL ATP. After the reactionwas complete, antibodies were added to test, the detection was performedwith Evnvision after incubation at room temperature for 60 minutes, anddata were collected. Data analysis and simulation were performed usingXLfit5 software.

Cell Experiment: Experimental Materials

RPMI 1640 medium, FBS fetal bovine serum and trypsin-EDTA were purchasedfrom Giboco. DPBS was purchased from Corning, penicillin/streptomycinsolution from Hyclone, Cell-Titer Glo reagent from Promega (1 kit, Cat.No. G7571). PC-9 was built by WuXi itself. Plate reader: Envision(Perkin Elmer).

Experimental Methods:

45 μL Culture media was added to columns 1, 2, 24 of a 384-well plate,repectively. The cell suspension was separated by Multi-drop, 45 μL(1000 cells) per well, which was placed and cultured in an incubatorovernight. A compound was added to the source plate according to therequirement of Echo liquid-separation. The compound in the source platewas added to the interplate and diluted to an intermediateconcentration, then the compound in the source plate and the interplatewas added to the cell plate, and the cells were further cultured in theincubator for 72 hours. After 72 hours, Cell-Titer Glo reagent and cellswere taken out and equilibrated at room temperature for 30 minutes. 25μL Cell-Titer Glo reagent was separated into the cells in 384-well plateby Multi-drop, shaken at medium speed for 3 minutes, centrifuged at 1000rpm for 2 minutes, and kept for 10 minutes. Envision was used to readthe plate (Luminescence).

IC 50 values of wild-type EGFR enzyme, EGFR exon 19 deletion enzyme,EGFR L858R enzyme, anti-PC-9 cell proliferative activity, anti-HCC827cell proliferative activity and anti-A431 cell proliferative activity ofthe compounds of the present invention are shown in the following table.

Anti-PC-9 (Δ19del) Anti-A431 EGFR cell cell Wild-type exon 19 EGFRprolif- prolif- EGFR deletion L858R erative erative enzyme enzyme enzymeactivity activity IC₅₀ IC₅₀ IC₅₀ IC₅₀ IC₅₀ Compounds (nM) (nM) (nM) (nM)(nM) Formate of — 16.5   48.1 165 — compound 2 Formate of — 0.02  0.1 396   compound 3 Formate of — 55.4   30.1 396 — compound 4 Formate of — —— 2.725 — compound 5 Formate of <0.015  0.070 — 4.900 — compound 6Formate of — — — 6.012 73.0 compound 10 Formate of 0.017 0.085 — 9.11346.0 compound 12 Formate of 0.016 0.052 — 5.340 — compound 13 Formate of— — — 23.020 — compound 15 Compound 16 — — — 539.587 — Formate of — — —29.385 — compound 17 Compound 18 <0.015  0.050 — 12.534 59.0 Formate of— — — 1280.181 — compound 19 Formate of — — — 2.166 — compound 20Formate of — — — 2.961 — compound 21 Formate of — — — 41.401 — compound22 Compound 23 0.038 0.170 — 23.961 — Formate of — — — 7.534 — compound24 Compound 25 0.022 0.069 — 6.756 64.0 Compound 26 — — — 7.202 98.0Compound 27 — — — 84.027 — Formate of — — — 249.975 — compound 28Compound 29 — — — 14.662 — Hydrochloride 0.021 0.052 — 11.177 71.0 ofcompound 30 Hydrochloride — — — 15.279 — of compound 31 Formate of 0.1140.290 — — — compound 33 Compound 37 — — — 21.2 — Compound 38 — — — 24.9— Compound 39 — — — 16.8 — Compound 41 — — — 5.74 — Compound 45 — — —8.86 — Formate of — — — 29.8 — compound 46 Formate of — — — 8.55 —compound 48 Compound 49 — — — 4.20 — Note: “—”means not tested

Conclusion: Since EGFR autophosphorylation, i.e. dimerization, canactivate the kinase pathway in cells, the autophosphorylation can leadto downstream phosphorylation and induce cell proliferation. There ishigh or abnormal expression of EGFR in many tumors, which plays animportant role in the progression of malignant tumors. Inhibition ofPC-9 (19del) cell activity can most intuitively reflect theanti-proliferative effect of compounds on an exon 19 deletion cellmodel, so as to screen compounds in vitro. It can be seen from the tablethat the compounds of the invention show very high anti-proliferativeactivity against PC-9 (19del) cells.

1. A compound of formula (I) or a pharmaceutically acceptable saltthereof,

wherein, R₁ and R₂ are independently selected from H, halogen, OH, CN,NH₂, respectively, or selected from C₁₋₅ alkyl and C₁₋₅ heteroalkyl,C₁₋₅ alkyl and C₁₋₅ heteroalkyl being optionally substituted with one,two or three R; or, R₁ is connected with R₂ to form a 4-6-membered ringsubstituted with two R₅; L₁ is selected from a single bond,—(C(R)₂)_(m)—, —O(C(R)₂)_(m)—, —S(C(R)₂)_(m)—; m is independentlyselected from 0, 1, or 2, respectively; R₅ is independently selectedfrom H, halogen, OH, CN, NH₂, respectively, or independently selectedfrom C₁₋₅ alkyl, C₁₋₅ heteroalkyl, C₃₋₆ cycloalkyl and 3-6-memberedheterocycloalkyl, C₁₋₅ alkyl, C₁₋₅ heteroalkyl, C₃₋₆ cycloalkyl and3-6-membered heterocycloalkyl being optionally substituted with one, twoor three R; R₃ is selected from H, or selected from C₁₋₃ alkyl, C₁₋₃heteroalkyl, C₁₋₃ alkyl and C₁₋₃ heteroalkyl being optionallysubstituted with one, two or three R; L₂ is selected from the groupconsisting of a single bond, —O—, —NH—; L₃ is selected from the groupconsisting of —C(R)₂—; ring A is selected from the group consisting ofphenyl, 5-10-membered heteroaryl; R₄ is independently selected from thegroup consisting of H, halogen, C₁₋₃ alkyl, C₁₋₃ heteroalkyl, C₂-3alkynyl, respectively; R is independently selected from H, OH, CN, NH₂,halogen, respectively, or selected from C₁₋₃ alkyl and C₁₋₃ heteroalkyl,C₁₋₃ alkyl and C₁₋₃ heteroalkyl being optionally substituted with one,two or three R′; the “hetero” of said C₁₋₅ heteroalkyl, said C₁₋₃heteroalkyl, said 3-6-membered heterocycloalkyl, said 5-9-memberedheteroaryl is selected from the group consisting of —O—, ═O, N, —NH—,—S—, ═S, —S(═O)—, —S(═O)₂—, —C(═O)O—, —C(═O)NH—, —S(═O)NH—; R′ isselected from the group consisting of F, Cl, Br, I, OH, CN, NH₂; in anyof the above cases, the number of heteroatoms or heteroatom-containinggroups is independently selected from 1, 2 or 3, respectively.
 2. Thecompound or pharmaceutically acceptable salt thereof according to claim1, wherein, R is selected from the group consisting of H, F, Cl, Br, OH,CN, NH₂, CH₃, CH₃CH₂, CH₃O, CF₃, CHF₂, CH₂F.
 3. The compound orpharmaceutically acceptable salt thereof according to claim 1, wherein,R₁ and R₂ are independently selected from H, halogen, OH, CN, NH₂,respectively, or selected from CH₃, CH₃CH₂, CH₃O, CH₃NH, (CH₃)₂N,(CH₃)₂NCH₂ and CH₃OCH₂, CH₃, CH₃CH₂, CH₃O, CH₃NH, (CH₃)₂N, (CH₃)₂NCH₂and CH₃OCH₂ being optionally substituted with one, two or three R. 4.The compound or pharmaceutically acceptable salt thereof according toclaim 3, wherein, R₁ and R₂ are independently selected from the groupconsisting of H, F, Cl, Br, OH, CN, NH₂, CH₃, CH₃CH₂, CH₃O, CH₃NH,(CH₃)₂N, (CH₃)₂NCH₂, CH₃OCH₂, respectively.
 5. The compound orpharmaceutically acceptable salt thereof according to claim 1, wherein,L₁ is selected from a single bond, —O—, —S—, —C(R)₂—, —(C(R)₂)₂—,—OC(R)₂— and —O(C(R)₂)₂—.
 6. The compound or pharmaceutically acceptablesalt thereof according to claim 5, wherein, L₁ is selected from a singlebond, —O—, —S—, —CH₂—, —(CH₂)₂—, —CH₂O— and —(CH₂)₂O—.
 7. The compoundor pharmaceutically acceptable salt thereof according to claim 1,wherein, the structural unit

is selected from:


8. The compound or pharmaceutically acceptable salt thereof according toclaim 7, wherein, the structural unit

is selected from:


9. The compound or pharmaceutically acceptable salt thereof according toclaim 1, wherein, the structural unit

is selected from:


10. The compound or pharmaceutically acceptable salt thereof accordingto claim 9, wherein, the structural unit

is selected from:


11. The compound or pharmaceutically acceptable salt thereof accordingto claim 1, wherein, R₅ is independently selected from the groupconsisting of H, F, Cl, Br, OH, CN, NH₂, respectively, or selected fromCH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O, CH₃OCH₂, N(CH₃)₂, NH(CH₃),

CH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O, CH₃OCH₂, N(CH₃)₂, NH(CH₃),

being optionally substituted with one, two or three R.
 12. The compoundor pharmaceutically acceptable salt thereof according to claim 11,wherein, R₅ is independently selected from the group consisting of F,Cl, Br, OH, CN, NH₂, CH₃, CH₃CH₂, CH₂CH₂F, CH₃CH₂CH₂, CH₃O, CH₃OCH₂,N(CH₃)₂,

respectively.
 13. The compound or pharmaceutically acceptable saltthereof according to claim 10, wherein, the structural unit

is selected from:


14. The compound or pharmaceutically acceptable salt thereof accordingto claim 1, wherein, R₃ is selected from H, CH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃Oand CH₃OCH₂, or selected from CH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O and CH₃OCH₂,CH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O and CH₃OCH₂ being optionally substitutedwith one, two or three R.
 15. The compound or pharmaceuticallyacceptable salt thereof according to claim 14, wherein, R₃ is selectedfrom the group consisting of H, CH₃, CH₃CH₂, CH₃CH₂CH₂, CH₃O, CHF₂O,CH₃OCH₂.
 16. The compound or pharmaceutically acceptable salt thereofaccording to claim 1, wherein, R₄ is independently selected from thegroup consisting of H, F, Cl, Br, I, CH₃, CH₃O and CH≡C—, respectively.17. The compound or pharmaceutically acceptable salt thereof accordingto claim 1, wherein, ring A is selected from the group consisting ofphenyl, thienyl, pyrrolyl, furyl, pyridyl, indolyl and benzimidazolyl.18. The compound or pharmaceutically acceptable salt thereof accordingto claim 1, wherein

is selected from:


19. The compound or pharmaceutically acceptable salt thereof accordingto claim 1, wherein the compound is selected from:

wherein, R₁, R₂, R₃, R₄ are as defined in claim
 1. 20. The compound orpharmaceutically acceptable salt thereof according to claim 19, whereinthe compound is selected from:

wherein, R, R₃, R₄, R₅ are as defined in claim
 19. 21. The compound,which is selected from:


22. The compound according to claim 21, which is selected from:


23. A pharmaceutical composition, comprising a therapeutically effectiveamount of the compound or pharmaceutically acceptable salt thereof orpharmaceutically acceptable carrier thereof according to claim
 1. 24. Amethod for treating cancer, comprising administering a therapeuticallyeffective amount of the compound and pharmaceutically acceptable saltthereof according to claim 1 to a subject in need thereof.